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.

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:

• 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

Development of fully human MAbs required the invention of special technologies (phage display or the humanized mouse) that do not rely on mouse hybridoma technology.

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.

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.

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

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.