Pharma NewsBytes (August, 2003)

LeadDiscovery's intelligence service, DailyUpdates has evolved as a key tool to help all in the drug development sector keep track of breaking journal articles, press releases and pharmaceutical reports. Pharma NewsBytes features selected press releases recently featured on DailyUpdates and offers the reader a leisurely stroll through the past few weeks of activity from within the pharmaceutical industry.

• US FDA panel backs AstraZeneca cholesterol drug[more]
• Desitin and G2M Cancer Drugs sign development agreement on novel cancer treatment[more]
• Roche Researchers Discover Potential New Treatment for Type 2 Diabetes; Researchers Identify New Class of Drug[more]
• Roche buys experimental drug from Cardion[more]
• Complete Remission of Tumors Reported in Patients with Primary Liver Cancer[more]
• Amylin Pharmaceuticals Reports Encouraging Phase 2 Results From GLP-1 Program In Severe Congestive Heart Failure[more]

On July 9 AstraZeneca announced that their cholesterol pill Crestor, the company's biggest new drug hope, had cleared a major hurdle as a U.S. advisory panel unanimously supported its approval. This news is considered of key importance to the pharmaceutical industry since its peak sales are predicted to hit $3 billion worldwide, 20% of the huge worldwide market for statins, which now stands at about $19 billion per year. Crestor is claimed by AstraZeneca to work better than currently marketed statins like Pfizer's Lipitor, Merck & Co's Zocor, and Bristol-Myers Squibb's Pravachol. Lipitor is the top-selling drug in the world, with sales of about $8 billion in 2002. One study comparing Crestor and Lipitor showed various doses of Crestor reduced LDL by 46 to 55 percent, while various Lipitor doses cut LDL by 37 to 51 percent. The FDA is expected to decide by August 12 whether to approve Crestor, company officials said. FDA staff who reviewed the drug had expressed concerns about possible kidney side effects with Crestor's 40 milligram dose because some patients' urine had elevated protein levels. AstraZeneca said the elevations were reversible and had not been shown to impair kidney function at the 40 milligram dose. Still, the advisory panel agreed that doctors should watch for kidney toxicity in patients taking the highest dose. Crestor already is approved in 24 countries, including Canada and parts of Europe, but U.S. approval was delayed after regulators last year asked for more information [more].

The need for improved treatments of cancer has driven the development of a number of strategies designed to regulate transcription. Histone deacetylation represents an emerging area of transcriptional control receiving much interest. This field centers on the now generally accepted view that chromatin structure is plastic and that histone (de)acetylation regulates genome structure and hence expression. Modifying this process by histone deacetylase (HDAC) inhibitors can therefore regulate, potentially in a highly specific manner, transcription thereby offering a much more targeted approach to cytostasis than currently available. Information relating to histone deacetylation is emerging with breathtaking rapidity with over 1 new article currently being published every day. In response to this activity LeadDiscovery recently published a comprehensive overview of the pharmaceutical potential of HDAC inhibitors (Click here to access "Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer"). Despite the body of data surrounding the use of HDAC inhibitors the development of therapeutic candidates is yet to take off. The recent agreement announced July 15th between Desitin and G2M is therefore of considerable interest. Under the terms of this agreement, Desitin will be responsible for the development of a tailor made formulation of G2M's HDAC inhibitor G2M-777 for cancer indications. Although Desitin has a primary focused on CNS disease they also have considerable experience in drug delivery. This along Desitin's strengths in marketing and distribution of CNS Rx pharmaceuticals appears to be a primary driver in this collaboration [more].

July 17th - Researchers at Roche have discovered a new class of drugs which, in preclinical studies, increase the efficiency of an enzyme critical to maintaining the normal balance of glucose in the body. This discovery represents a potential new treatment for the more than 135 million people who are afflicted with type 2 diabetes worldwide (click here for a full report on diabetes). Patients with type II diabetes have too little insulin and produce too much glucose. "The glucokinase (GK) enzyme is the body's first step in breaking down or metabolizing glucose," explained Joseph Grippo, Ph.D., Roche vice president, Metabolic Diseases. "When the enzyme is functioning normally, GK helps the body maintain glucose levels by controlling the release of insulin from the pancreas as well as the disposal of glucose in the liver." In their recent Science article (click here) Grippo and his team of scientists identified and developed a new class of drugs -- called glucokinase activators (GKAs) -- that increase the efficiency, or activate, this pivotal enzyme, and in doing so lowers blood sugar in preclinical models of type 2 diabetes. He said the GKA compound is unique because it stimulates the pancreas to release more insulin and also keeps the liver from producing too much glucose. Currently many diabetic patients are given two medications to achieve this dual action: sulfonylureas and metformin. Both of these drugs were discovered over 25 years ago, and are still used as first-line anti-diabetes treatments. "By being able to activate the GK enzyme, we may be able to provide a mechanism to improve both defects commonly found in type 2 diabetes, namely insulin release and hepatic [liver] glucose metabolism," said Joseph Grimsby, Ph.D., Roche's preclinical GKA project leader and primary author of the Science article, Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy. "Roche's discovery and preclinical findings support the important role GK plays as a glucose sensor and suggest that pharmacological activation of GK activity could have important clinical benefits in type 2 diabetes," added Franz Matschinsky, M.D., of the Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, and editor-in-chief of Diabetes. He also contributed to the Science paper. Roche's interest in the GK enzyme followed a key discovery made in 1992 that showed a small subset of diabetes, known as maturity onset diabetes of the young type 2 (MODY2), is caused by mutations in the GK gene. Preclinical findings provided strong biological rationale for considering GK as a target for drug discovery efforts. The Roche team screened 120,000 compounds and found one that seemed to activate GK. An important test with this early compound proved that GK activation works, giving the green light to move additional generations of GKA compounds through the Roche pipeline. Even though there is much work ahead, confidence is strong that this new class of glucose activators could play an important role as hypoglycemic agents in the treatment of type 2 diabetes. Type 2 diabetes is such a huge unmet medical need. It is predicted that 300 million people will be diagnosed with this serious disease by 2025. "It is quite rare and very exciting to be involved in a drug with this kind of potential to dramatically impact the lives of patients," added Grimsby. "The GK enzyme is pivotal as a key controller of glucose homeostasis (balance) in all people, so being able to activate this natural control point has enormous potential for all patients with type 2 diabetes," said Grippo [more]

A separate development brought Roche into the news a few days later on July 22 when it was announced that they had agreed to buy an experimental drug from Germany's Cardion AG that aims to treat rheumatoid arthritis and transplant patients. The agreement focussed on Cardion's human Interleukin IL-15 Cytokine Receptor Blocker (CRB-15) drug, now in pre-clinical development. "Under the terms of the agreement, Cardion will receive an initial payment as well as additional milestone-based payments which could reach up to $90 million if all development event milestones are met," Roche said in a statement. "In addition, Roche will pay Cardion royalties based upon future product sales." Roche will be responsible for development and worldwide commercialisation of CRB-15 and will get intellectual property rights to the compound. Roche said the deal would strengthen its transplantation franchise and build on its pipeline of products for treating rheumatoid arthritis, a chronic autoimmune disease that inflames joints and erodes bones in the nearly six million people who suffer the ailment. Roche is also developing its top-selling cancer drug MabThera for treating rheumatoid arthritis and has licensed in a rheumatoid arthritis drug called MRA from its separately listed Japanese subsidiary Chugai. Roche will develop and promote MRA, which is in late-stage clinical trials, jointly with Chugai. Roche's portfolio of transplant drugs had sales of 1.5 billion Swiss francs ($1.10 billion) in 2002, up 16 percent from the year before. CRB-15 was invented by researchers at Beth Israel Deaconess Medical Centre in Boston. Cardion got CRB-15 through the acquisition of Tolerance Pharmaceuticals Inc in 2001 [more].

July 23 - Phoenix Pharmacologics, a privately held biopharmaceutical company specializing in targeted-enzyme therapy of cancer, reported results of a phase II clinical study with a protein known as arginine deiminase (ADI). This enzyme degrades the amino acid arginine, which circulates in the blood and is required by certain tumors for their growth. Hepatocellular carcinoma (HCC) is one of these tumors for which there is no effective treatment. The trial was conducted in Italy in patients with HCC whose tumor was rapidly progressing and who had only a few months to live. Patients were treated once weekly for 3 months and continued to be examined monthly by CT scans for status of their disease. Of the 19 patients, 2 are in complete remission without any clinical evidence of disease, 7 have experienced > 50% remission of their tumor, and 7 had stable disease with no increase in tumor size. In the 6 months since the end of treatment, 14 continue to derive medical benefit from treatment. Their average survival was greater than 5 times the historical life expectancy for comparable patient populations. Clinical investigator Francesco Izzo MD, from the Pascale National Cancer Institute, Naples, Italy commented, "We have seen major decreases in the tumor masses and a dramatic increase in the quality of life of our patients. They feel so much better and are leading much more productive lives. Some have even returned to their full time employment." Dr. Izzo further commented, "The treatment with ADI is no more painful than a vaccination and any toxic effects are very mild and essentially non-significant. We are very enthusiastic about continuing our clinical investigations in HCC and other tumor types, such as metastatic melanoma that are sensitive to ADI treatment." Phase 3 testing of ADI in a larger patient population with HCC is expected to begin in September in Europe and the study is to be complete by the middle of next year. Additionally, Dr. Steven Curley, Head of GI Surgical Oncology, MD Anderson Cancer Center, The University of Texas Medical Center, Houston, TX., who is performing the Phase 2 testing of ADI in the USA commented, "We have used ADI in some of our patients who had very large tumors which were not amenable to surgery. Shrinkage of the tumor enabled complete surgical resection of the tumor and allowed the patient to resume a normal life, including a continued career and work schedule. We view ADI as not only an effective single agent treatment for HCC, but a very safe drug which may be used alone or combined with other drugs and therapeutic modalities to potentially bring benefit to patients with other types of tumors as well." This drug was developed at Phoenix Pharmacologics by individuals who have experience in recombinant protein production and scale up, enzymology, and the formulation of proteins with polyethylene glycols. CEO and Chief Scientist, Dr. Mike Clark added, "We approached the problem by identifying a specific viable target in tumor cells and then tested a large number of different formulations of molecules that produced the end result of starvation and death to the tumor cell. We view ADI-PEG as a deadly 'rifle shot' to the tumor cell and not a 'shotgun blast' that kills normal body cells along with the tumor cells. Hence, our anticancer therapeutics are not only effective, but also very safe and non-painful for use in treating patients. We anticipate rapid approval of ADI in the USA once a suitable pharmaceutical company partner can be identified to assist in completing the pivotal clinical phase 3 trial and commercialization of the product" [more].

July 29 - Amylin Pharmaceuticals announced encouraging results from a Phase 2 dose- titration study of drug candidate AC2592, which utilizes continuous subcutaneous infusion of glucagon-like peptide 1 (GLP-1) for the treatment of congestive heart failure (CHF) in patients ineligible for transplant. GLP-1 is a naturally occurring hormone produced in the gut. This open-label exploratory study included 14 subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure, all of whom received study medication. Subjects were followed for 12 weeks and monitored on a number of parameters. Outcome measures included peak oxygen consumption, left ventricular ejection fraction, quality of life assessment, and brain natriuretic peptide, or BNP (an indicator of heart dysfunction). Subjects received infusion of AC2592 at an introductory dose for the first week, a higher-level infusion of AC2592 for weeks 2 through 5, the maximum infusion dose for weeks 6 through 9, and no medication from weeks 10 through 12. Subjects showed general improvement in a composite score designed to quantify quality of life and cardiac function while receiving study medication. The score returned to baseline when medication was discontinued. The severity of heart failure, as indicated by NYHA class, also improved during AC2592 administration. The most common adverse event reported was mild to moderate nausea. "The results of this study suggest that AC2592 has the potential to benefit patients with severe congestive heart failure and support continuation of the program," said Alain Baron, MD, Senior Vice President, Clinical Research at Amylin. "We continue to improve our understanding of the function and characteristics of gut hormones and are encouraged by the potential this novel application of the GLP-1 hormone shows as a metabolic approach to treating CHF." Congestive heart failure occurs when the heart cannot sufficiently pump oxygenated blood throughout the body, resulting in impaired kidney function and an accumulation of fluid in the lungs and other body tissues. CHF can be caused by common conditions such as ischemic heart disease, high blood pressure and diabetes, and carries a risk of morbidity and mortality. Nearly 5 million people in the US are living with congestive heart failure, of which approximately 80,000 are transplant ineligible. Amylin Pharmaceuticals is a biopharmaceutical company dedicated to developing innovative medicines to improve the lives of people with metabolic diseases. Building on its experience in the diabetes field, the Company is developing candidates for cardiovascular disease and obesity by utilizing its research experience with the metabolic properties common to all three conditions.[more].