I will lead a workshop entitled “Developing Improved Animal Models in Oncology and CNS Diseases to Increase Drug Discovery and Development Capabilities” at the World Drug Targets Summit in Cambridge MA in July 2011.

Workshops will be held on July 19, and the main conference on July 20-21. I am planning to attend the entire conference.

Our workshop will be a discussion of 2-3 case studies involving development of novel animal models in oncology and CNS diseases, aimed at more closely modeling human disease than current models. Drug discovery and development in these therapeutic areas has been severely hampered by animal models that are  poorly predictive of efficacy. This is a major cause of clinical attrition in these areas.

We shall discuss the implications of these case studies for developing novel therapeutic strategies, target identification and validation, drug discovery, preclinical studies, and reducing clinical attrition. We shall also discuss hurdles to industry adoption of novel animal models developed in academic laboratories.

The main conference will focus on ways of building successful target strategies to minimize drug attrition in the clinic, and specifically how to identify and validate targets that can lead to commercially differentiated products. Speakers will include target discovery and validation leaders from such companies as Pfizer, Merck, NeurAxon, Gilead Sciences, Boehringer Ingelheim, Merrimack Pharmaceuticals, Bayer Schering Pharma AG, FORMA Therapeutics, Roche, Novartis, Tempero Pharmaceuticals, UCB Pharma, Infinity Pharmaceuticals, and from such academic institutions as Harvard Medical School.

The conference agenda and brochure, as well as online registration, are available on the conference website.

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

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

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

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

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

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

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

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

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

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

Dr. Birnbaum’s analysis

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

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

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

Dr. Shaw’s analysis

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

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

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

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

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

Our conclusions

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

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

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

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

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

___________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Melanoma

On March 25, 2011, the FDA approved ipilimumab (Medarex/Bristol-Myers Squibb’s [BMS’s] Yervoy) for treatment of unresectable or metastatic melanoma. The drug has been approved for patients with either newly-diagnosed or previously-treated disease.

According to Richard Pazdur, the director of the FDA’s office of oncology drug products, none of the previously-approved treatments for metastatic melanoma, a disease with a poor prognosis, prolonged a patient’s life. “Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment.”

We discussed ipilimumab briefly in a previous article on this blog. As we stated in that article, the results of a Phase 3 trial of ipilimumab were published in the August 19, 2010 issue of the New England Journal of Medicine.  Ipilimumab is an immunomodulator that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) to potentate an antitumor T-cell response. The drug is a monoclonal antibody (MAb). In this NEJM article, the researchers reported that ipilimumab treatment–given with or without a gp100 peptide vaccine–showed a median overall survival of 10 months, as compared to 6.4 months in patients receiving gp100 alone. Ipilimumab treatment also gave improved one-year survival compared with gp100 alone–46% versus 25%. Two-year survival was 24% in the ipilimumab group and 14 percent in the gp100 group.

Decision Resources published our report on development of immunomodulators in treatment of cancer in 2007. This report includes a discussion of ipilimumab, and provides further information on its mechanism of action, adverse effects, etc., as well as on other immunomodualtors for treatment of cancer, some of which are now on the market.

BMS plans to report on the results of a later Phase 3 study, which also demonstrated significantly improved survival as compared to a control treatment, at the American Society of Clinical Oncology (ASCO) meeting in Chicago in June.

In its March 25, 2011 press release, BMS said that it had agreed with the FDA to conduct a post-marketing study comparing the safety and efficacy of the 3 mg/kg dose vs. an investigational 10 mg/kg dose in patients with unresectable or metastatic melanoma.

The Full Prescribing Information for ipilimumab will include a boxed warning for immune-mediated adverse effects. Ipilimumab treatment can result in severe or fatal immune-mediated adverse effects, especially enterocolitis, hepatitis, dermatitis, neuropathy, or endocrinopathy. These are usually reversible by discontinuing  ipilimumab therapy and treatment with high-dose steroids. According to the FDA, severe to fatal autoimmune reactions were seen in 12.9% of patients treated with the drug.

As part of the approval of ipilimumab, BMS is collaborating with the FDA to develop a Risk Evaluation and Mitigation Strategy,  to help inform patients and providers about these safety risks. The company  has put in place a system that will enable it to deliver these educational materials to healthcare professionals at the time they order the drug.

Strategic implications for BMS

BMS has hailed the approval of ipilimumab as a victory for its strategic changes over the past several years. The company has been focusing on its pharmaceutical business, selling off such nonpharmaceutical assets as the Mead Johnson Nutrition Company (MJN), and instituting other cost-cutting measures. BMS has at the same time been developing its “String of Pearls” strategy. In this strategy, BMS has been forming a series of acquisitions, alliances and partnerships with biopharmaceutical companies, involving both small molecules and biologics. According to BMS, the String of Pearls strategy has enabled BMS to expand its pipeline by nearly 40 percent. About one-third of BMS’ pipeline drugs are now biologics.

We have discussed the String of Pearls strategy, and two acquisitions that have been part of it, on this blog. These were the acquisition of Medarex (the largest of the “pearls”), and the newest acquisition, ZymoGenetics. It was MAb-therapeutic leader Medarex, now a wholly-owned subsidary of BMS, that initially developed ipilimumab.

BMS faces the expiration of patent protection for its best-selling product,  the anticlotting drug Plavix, in 2012. The introduction of ipilimumab, which several analysts expect to become a blockbuster, should help mitigate the results of the Plavix patient expiration. However, ipilimumab is not likely to fully replace the lost sales due to generic competition with Plavix. Moreover, the approval of one drug–ipilimumab–does not necessarily mean that BMS’ new R&D strategy, based on the String of Pearls acquisitions and partnerships, will yield a rich series of important approved drugs in the next 5-10 years. However, ipilimumab itself is such an important drug, in terms of its path-breaking mechanism of action, its addressing unmet medical need in a fatal disease, and its likely blockbuster status.

Another melanoma drug is on the way

The Biopharmconsortium Blog has been following the development of Daichi Sankyo/Plexxikon/Roche’s PLX4032/RG7204 (now designated as vemurafenib) for about a year. We have published several articles on the drug and on related scientific, clinical trial strategy, and business issues. This targeted kinase inhibitor, which is exquisitely specific for the melanoma driver mutation B-Raf(V600E), has been in Phase 3 clinical trials, and its developers filed for U.S. and European approval in May 2011. The drug is expected to reach the market in 2012. As with ipilimumab, Plexxikon and Roche reported that a Phase 3 trial of PLX4032 gave enhanced overall survival as compared with treatment with the standard of care, dacarbazine. The companies also plan to present the results of this trial at the ASCO meeting in June.

Metastatic melanoma patients, who have had few options for treatment, will now have two new, breakthrough drugs that can give them additional months of life, and in some cases longer. However, no treatment now on the horizon will result in long-term survival. In the case of PLX4032, this is due to the development of resistance to the drug. As we discussed previously, researchers are studying mechanisms of PLX4032 resistance, and developing potential combination therapies to overcome it. A clinical trial of at least one combination therapy, in collaboration with Genentech, is planned to begin soon.

A new approach to PLX4032-based combination therapy for melanoma

Meanwhile, another approach to development of an effective combination therapy with PLX4032 comes from an unexpected source.

We had discussed a zebrafish model of melanoma, developed by Leonard Zon’s laboratory at Children’s Hospital/Howard Hughes Medical Institute/Harvard Medical School (Boston, MA), in our 2010 Insight Pharma Report Animal Models for Therapeutic Strategies. In this model, the researchers created transgenic zebrafish strains in which B-Raf(V600E) is expressed under control of the melanocyte-specific mitfa promoter. Wild-type zebrafish expressing B-Raf(V600E) in their melanocytes developed benign nevi, while those with germline mutations in p53 may develop either nevi or melanomas. This suggests these two mutations are necessary, but not sufficient, to cause melanoma. (In humans, nevi may express B-Raf(V600E), which also indicates that it is not sufficient to cause melanoma. And in human melanomas, p53 is either mutated or otherwise rendered inactive.)

Now, in the 24 March issue of Nature, Dr. Zon and his colleagues used this model to study the mechanism of tumorigenesis in melanoma. They found that early-stage embryos of the transgenic zebrafish showed abnormal expansion of neural crest progenitors, and that these progenitors failed to terminally differentiate. (Melanocytes are one of the cell types that develop from the neural crest lineage.) In adult transgenic zebrafish, melanomas develop and are positive for neural crest progenitor markers, and thus appear to retain a neural crest progenitor-like phenotype.

The researchers therefore screened 2,000 compounds to identify those that act as suppressors of neural crest progenitors, without displaying toxicity. The one compound that satisfied these criteria, NSC210627, was similar to brequinar, an inhibitor of dihydroorotate dehydrogenase (DHODH), and NSC210627 also inhibited DHODH in vitro. The researchers therefore tested another more readily-available DHODH inhibitor, leflunomide (Sanofi-Aventis’ Arava). It had the same effects on the zebrafish as NSC210627 and was used for further studies.

Leflunomide treatment resulted in a nearly complete inhibition of neural crest development in zebrafish embryos, and specifically resulted in abrogation of melanocyte development both in zebrafish embryos and in Xenopus (African clawed frog) embryos. The drug’s target, DHODH, catalyzes a step in the synthesis of pyrimidine nucleotides, and thus inhibits transcriptional elongation. The researchers found that leflunomide caused specific defects in the transcriptional elongation of genes necessity for neural crest development in zebrafish. In human melanoma cell lines, leflunomide also inhibited transcriptional elongation in genes necessary for neural crest development and for melanoma growth (e.g, the Myc oncogene, which is required for both processes). Leflunomide (or its active metabolite, A771726) caused inhibition of growth both of human melanoma cell lines in vitro and in vivo in mouse xenograft models, but had little effect on non-melanoma cell lines in vitro. Combined treatment with leflunomide and PLX4032 showed even greater inhibition of growth of human melanoma cells in vitro and in vivo than treatment with either single agent.

Leflunomide is a marketed drug that is approved for treatment of moderate to severe rheumatoid arthritis and psoriatic arthritis. In these diseases, it appears to work via inhibiting the expansion of autoimmune lymphocytes by inhibiting transcriptional elongation in specific genes in these cells. Although leflunomide can have serious adverse effects in a minority of patients (e.g., liver damage), it has a generally favorable safety profile. Dr. Zon and his colleagues suggested that combination therapy of patients whose tumors are positive for B-Raf(V600E) with PLX4032 and leflunomide would be more effective than treatment with either drug alone, and that this combination therapy might help to overcome PLX4032 resistance.

Since leflunomide is already approved by the FDA, and both leflunomide and PLX4032 have been proven to be safe in clinical trials, researchers should be able to readily initiate clinical trials of the combination therapy. Dr. Zon says that  he is now working toward initiation of a clinical trial of the drug combination.

________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

On March 1, 2011, Plexxikon, Inc. (Berkeley, CA) announced that it has agreed to be acquired by Daiichi Sankyo, Japan’s third-largest pharmaceutical company, via an all-cash purchase. Under the merger agreement, Daiichi will pay $805 million up-front to purchase Plexxikon. Near-term milestone payments associated with the approval of Plexxikon’s lead drug candidate PLX4032 could total an additional $130 million.

The main driver for the merger is Plexxikon’s lead drug, PLX4032, for the treatment of metastatic melanoma. Plexxikon and its development and commercialization partner Roche/Genentech expect to file for U.S. and European approval of PLX4032 this year; the drug is expected to reach the market in 2012. By acquiring Plexxikon, Daiichi will gain the right to co-promote the drug in the U.S. with Genentech. PLX4032 is a novel oral drug that specifically targets B-Raf kinase carrying the V600E mutation, which is present in the majority of human melanomas.

We have been covering the development of PLX4032 on the Biopharmconsortium Blog. Our most recent article, “Phase 3 trial of targeted anticancer drug PLX4032/RG7204 shows overall survival benefit in melanoma patients”, was posted on January 23, 2011. That article, which discusses the successful Phase 3 trial of PLX4032 (which Roche has designated as RG7204), includes a list of links to our earlier articles. The Phase 3 trial showed that treatment with PLX4032 gave enhanced overall survival as compared with dacarbazine (the standard of care) in previously untreated metastatic melanoma patients carrying the B-Raf(V600E) mutation. Although previous studies showed tumor shrinkage and enhanced progression-free survival (by approximately seven months) in the majority of PLX4032-treated patients as compared to dacarbazine, this is the first report that PLX4032 give enhanced overall survival.

PLX4032 is a personalized medicine, which Plexxikon has planned to pair with a companion diagnostic, developed in partnership with Roche Molecular Diagnostics. The DNA-based companion diagnostic will identify patients whose tumors carry B-Raf(V600E). The companies plan to launch PLX4032 together with the companion diagnostic, so that oncologists can readily identify patients who would benefit from treatment with the drug.

In acquiring Plexxikon, Daiichi also gains a pipeline that includes the kinase inhibitor PLX3397, which is in Phase 1 safety studies, with Phase 2 studies planned in metastatic breast cancer, and PLX-204, an oral PPAR alpha, gamma, and delta partial agonist that is In Phase 2 clinical trials in type 2 diabetes.

Daiichi will also gain Plexxikon’s drug discovery and development technology and strategy. We discussed how Plexxikon used its proprietary scaffold-based drug design technology platform to discover PLX4032, in our March 10, 2010 article on this blog. Daiichi says that it plans to “provide a high degree of independence to the Plexxikon group to support their continuing success,” and to leverage Plexxikon’s technology platform to discover and develop newer drug candidates.

Daiichi’s purchase of Plexxikon is part of a recent trend, in which the leading Japanese pharmaceutical companies have been investing in  oncology R&D in the United States. Two of these investments were large acquisitions. In 2008, Takeda acquired Millennium Pharmaceuticals (Cambridge, MA) for $8.8 billion; Takeda operates its acquisition, renamed Millennium: The Takeda Oncology Company, as a wholly-owned subsidiary. Astellas acquired OSI (Melville, NY) for $4 billion in 2010; OSI also operates as a wholly-owned subsidiary.  Both of the acquired companies boast large-selling drugs–Millennium’s Velcade (bortezomib) and OSI’s Tarceva (erlotinib) (which is partnered with Genentech/Roche).

The Japanese pharmaceutical companies aim to utilize U.S. innovation to compete in the lucrative global oncology market, which analysts project will expand 12 to 15 percent per year, reaching as much as $80 billion by 2012. In contrast, annual sales growth for Japanese pharmaceutical companies is projected to average 1.4 percent from 2009 to 2015. Overseas investments by Japanese companies are also being driven by a strong yen; the yen gained 8 percent gain over the dollar during the past year.

Some analysts believe that Daiichi paid too much for Plexxikon, and that even with the Plexxikon acquisition, Daiichi will not be very competitive in oncology with Takeda and Astellas, each of which acquired much larger U.S. oncology companies. Moreover, Daiichi has other issues to deal with, such as slow sales for its oral antiplatelet agent Effient (Prasugrel) (codeveloped with Lilly, and approved in 2009), which Daiichi hoped would be a blockbuster drug. Moreover, Daiichi’s majority-owned Indian generic drug company Ranbaxy has experienced a fourth-quarter loss due to rising operating expenses.

In addition to its acquisition of Plexxikon, Daiichi is also codeveloping (with ArQule, of Woburn MA) ARQ 197, a c-Met kinase inhbitor; this compound is in Phase 3 clinical trials in non-small cell lung cancer (NSCLC). Daiichi also acquired German oncology firm U3 Pharma (Martinsried, Germany) for $235 million in 2008. U3 Pharma (which operates as a wholly-owned subsidiary of Daiichi) is developing MAb-based anticancer therapies. Daiichi also, in 2007, licensed Japanese development and commercialization rights to Amgen’s MAb drug denosumab. Denosumab, marketed as Xgeva, was approved in the U.S. in 2010 for prevention of skeletal-related events in patients with bone metastases of solid tumors.

Will the acquisition of Plexxikon help Daiichi to compete in the worldwide oncology market, with its Japanese rivals and with other pharmaceutical companies? Only time will tell. PLX4032 is an exciting, breakthrough medicine that is likely to be approved in 2012. Moreover, if Daiichi allows Plexxikon the freedom to innovate and invests in its R&D activity, and if it can also harness Plexxikon’s technology platform to discover and develop novel drugs across different therapeutic areas, the Plexxikon acquisition may prove to be a major competitive advantage despite its small size.

________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

“That’s all, folks!” http://bit.ly/gSgL6b

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

This followed the earlier rejections in 2010 by the Advisory Committee and the FDA of two other preregistration antiobesity drugs–Vivus’  Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. Concern about long-term safety was the major consideration in the rejection of Qnexa and lorcaserin, and safety issues (increased risk of cardiovascular events) were the reason for the withdrawal of sibutramine. Thus the Advisory Committee’s recommendation for approval of Contrave was surprising, to us as well as to many others.

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

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

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

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

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

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

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

Other established companies are pursuing different strategies, such as Amylin/Takeda’s development of pramlintide/metreleptin for obesity. This is really a metabolic syndrome-based approach to obesity. Indeed, Amylin (whose assets have passed on to AstraZeneca as of early 2014) had been developing metreleptin as a single agent for treatment of diabetes and high triglycerides in patients with lipodystrophy.

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

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

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

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

_______________________________________

As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.