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.

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.

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.

In the 10 July issue of Science, Jesse W.-H. Li and John C. Vederas of the University of Alberta reviewed the current state of natural products-based drug discovery and development, in a report entitled “Drug Discovery and Natural Products: End of an Era or an Endless Frontier?”

As of 1990, some 80% of marketed drugs were either natural products or analogues based on natural products. Two of the major families of natural products that have been of special interest to drug discovery researchers are the polyketides and the terpenoids. Examples of marketed polyketide drugs include the cancer drug doxorubicin, the antibiotic erythromycin, statins including lovastatin (Merck’s Mevocor) and derivatives such as simvastatin (Merck’s Zocor) and atorvastatin (Pfizer’s Lipitor), and the immunosuppressive drug rapamycin. Examples of marketed terpenoid drugs include paclitaxel (Bristol-Myers Squibb’s Taxol) and the cancer drugs vinblastine and vincristine.

During the 1990s and continuing to the present day, small-molecule drug discovery changed to emphasize libraries of synthetic organic compounds, for use in high-throughput screening (HTS). Many companies abandoned the field of natural products altogether. This was driven by pharmaceutical companies’ pursuit of blockbuster drugs, in order to produce the growth in revenues demanded by the companies’ shareholders.

As the fruits of genomics entered the pharmaceutical arena, HTS of synthetic compound libraries against genomics-derived targets became the governing paradigm of small-molecule drug discovery. Nevertheless, natural products and natural product derivatives still accounted for around 50% of newly approved drugs between 2005 and 2007. Over 100 natural products and natural product derivatives are now in clinical studies.

In the 1990s and 2000s, drug discovery researchers emphasized synthetic compounds over natural products because they are easy to synthesize, and are more amenable to use in HTS. They allow researchers to examine large numbers of compounds in a short amount of time. In contrast, natural products have complex structures, are often difficult to synthesize, may be present as small amounts of active compound in complex mixtures in their natural sources, and present a number of other difficulties. Nevertheless, hit rates with synthetic compound libraries are very low, less than 0.001%. For polyketide natural products, for example, hit rates have been about 0.3%.

Given the low output of marketed drugs (let alone blockbusters) emerging from the synthetic compound library-HTS-large scale genomics paradigm, drug discovery researchers may be drawn to look for alternatives that might give higher rates of productivity. We have spoken of biology-driven drug discovery as an alternative to large-scale genomics-driven drug discovery in earlier posts. This deals with the target discovery and validation side of drug discovery. Researchers may also want to look at the chemistry side of small-molecule drug discovery.

The authors of this review suggest that they take a new look at natural products. In their report, they review new technologies for gaining access to, screening, and synthesizing novel natural products and natural product derivatives. There are also a vast number of organisms that are yet to be explored for natural products with potential pharmaceutical activity. The authors of this review therefore believe that the field of natural product medicines may well experience a revival in the near future. The low productivity of the current paradigm of drug discovery may provide an additional impetus for researchers and companies to return to natural products as a source of new small-molecule drugs.

Among the technologies that the authors discuss is an application of synthetic biology known as metabolic engineering. This involves reengineering of natural metabolic pathways in microorganisms to produce useful pharmaceutical products, including difficult-to-synthesize natural products and novel natural product derivatives. Our report on synthetic biology, including metabolic engineering to produce terpenoid and polyketide natural products, was published by Decision Resources in 2007.

An example of a biotech company that had been commercializing the fruits of metabolic engineering is Biotica Technology (Cambridge, U.K.). Biotica had been using metabolic engineering to discover and develop polyketide natural product derivatives for treatment of such diseases as cancer, hepatitis C, asthma, and inflammation. (As of March 2013, NeuroVive (Lund, Sweden) acquired a portfolio of polyketide cyclophilin inhibitors from Biotica, which has gone out of business as of January 2013.)

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.