Transgenic plants offer hope for type 1 diabetes.

As reported in Autoimmune Market Outlook to 2012 autoimmune related disorders continue to maintain prominence within the global disease burden, having achieved a worldwide market growth of 9.4% over the 2002-06 period.

The autoimmune arena represents a key opportunity for drug development companies, with the potential for success largely attributable to substantial unmet demand, a significant patient population and the medical proclivity for long term treatments.

Type 1 diabetes is one high priority autoimmune disease as well as one of the most common chronic diseases in children and adolescents; about 151,000 American below the age of 20 years have diabetes and while a growing number of these individuals have type 2 diabetes the majority have type 1 disease. Diabetes often leads to long term complications, a problem that increases with duration of disease and so type 1 diabetes remains a particular concern. While good glucose control through injectable insulin is able to reduce the onset of complications in later life new strategies that can reverse the disease represent the holy grail of diabetology.

Interleukin-13 (IL-13) is a pleiotropic regulatory cytokine with the potential for treating several human diseases, including type 1 diabetes. However thus far, conventional expression systems for recombinant IL-13 production have proven difficult and are limited by efficiency. In an article from Plant Biotechnology Journal, soon to be highlighted on DailyUpdates, Wang et al report on the use of transgenic plants as a means of producing human IL-13 (hIL-13).

Transgenic plants represent an exciting opportunity in the emerging arena of biologics (see Transgenic Animals and Plants in Pharmaceutical Research and Manufacturing). With the mapping of the human genome and the concomitant explosion of proteomics, a steady stream of biopharmaceuticals have been launched. As the rate of regulatory approval for biopharmaceuticals increases, the number of products reaching the market will impose unprecedented demands on the industry’s biomanufacturing capacity. Whether or not this will create a biomanufacturing bottleneck is a hotly debated issue in the industry. One issue that is not debatable, though, is the high cost of manufacturing biopharmaceuticals. While biopharmaceuticals produced in bacterial or mammalian cell culture bioreactor facilities have proven to be very effective therapeutic agents, they are also among the most expensive drugs produced, and there is doubt that the current pricing models are sustainable regardless of these agents’ efficacy.

One way to address these concerns is through the use of transgenic plants to manufacture biopharmaceuticals.

Wang and colleagues have taken this approach producing DNA constructs containing hIL-13 cDNA that were introduced into tobacco plants. hIL-13 protein efficiently accumulated in transgenic plants with an expression level as high as 0.15% of total soluble protein in leaves. Multiple forms of plant-derived recombinant hIL-13 resulted from differential N-linked glycosylation. Of significant interest, plant rhIL-13 was highly resistant to proteolysis. In particular, resistance to gastric and intestinal fluid digestion was suggested.

These exciting findings suggest that not only can plants be harnessed to produce IL-13 at high levels reducing production costs, but also that the protein produced may be active orally removing the need for injection, a route of administration expected for such a molecule

Further development of this research is eagerly awaited as are studies establishing IL-13 as a therapeutic option for the treatment of type 1 diabetes

A hopeful future for Parkinson's disease patients

As discussed in our recent feature Parkinson's Disease Market analysis and forecasts Parkinson's disease is the second most common neurological disorder, affecting approximately 4.1m people worldwide.

Parkinson's disease is a neurodegenerative disorders characterized by the progressive loss of dopaminergic neurons and hence pharmacotherapy centers on bringing dopaminergic activity back to normal. The range of options open to Parkinson's disease patients is however changing.

Treatment of Parkinson's disease currently includes the use of levodopa, COMP inhibitors and dopamine agonists

Levodopa - the Gold Standard: Since its introduction in the 1960s, levodopa has been considered the gold standard drug therapy for Parkinson's disease. Levodopa is a precursor to dopamine that, when given to people with Parkinson's, is converted into dopamine by nerve cells in the brain. The increase in dopamine may reverse many of the disabling symptoms of Parkinson's disease.

Treatment with dopamine itself isn't possible, because dopamine doesn't cross the body's blood-brain barrier. Levodopa, on the other hand, does cross this barrier, but only a small amount actually reaches the brain. Today levodopa is generally combined with carbidopa that targets levodopa to the brain (by limiting its activation in the periphery) increasing the therapeutic index.

During early treatment, side effects from carbidopa-levodopa therapy are usually not a major problem. However, the drug works less evenly and predictably as the disease progresses. As a result, some people may experience involuntary movements (dyskinesia), primarily when the medication is having its peak effects. The length of time for which each dose is effective may begin to shorten (wearing-off effect), leading to more frequent doses.

Another problem that may develop with long-term carbidopa-levodopa usage, the on-off effect, may cause Parkinson's-related movement problems to appear and disappear suddenly and unpredictably. Other side effects may include hallucinations and a drop in blood pressure when standing (orthostatic hypotension). Some people may experience nausea with carbidopa-levodopa therapy.

COMT inhibitors as adjuncts to levodopa: Catechol-O-methyltransferase (COMT) inhibitors are often used alongside levodopa. COMT inhibitors prolong the effect of carbidopa-levodopa therapy by blocking an enzyme that breaks down dopamine. Tolcapone (Tasmar) is a potent COMT inhibitor that easily crosses the blood-brain barrier. But because Tasmar has been linked to liver damage and liver failure, the drug is normally used only in people who aren't responding to other therapies. Entacapone is a COMT inhibitor that shares some of the properties of tolcapone but doesn't cross into the brain. It may help manage fluctuations in the response to carbidopa-levodopa in people with Parkinson's disease. Entacapone doesn't cause liver problems and is now combined with carbidopa and levodopa in a medication called Stalevo.

Dopamine agonists as important components of the Parkinson's disease arsenal: Although carbidopa-levodopa typically allows people with Parkinson's disease to extend the time they are able to lead relatively normal lives and in many cases is effective for a number of years other treatment options are required. Dopamine agonists are used both as adjuncts to carbidopa-levodopa therapy. Bromocriptine and Permax suffered problems with adverse effects in the past however other dopamine agonists such as romocriptine (Parlodel), apomorphine (Apokyn), pramipexole (Mirapex) and ropinirole (Requip) are all still used.

Selegiline as a strategy for delaying carbidopa-levodopa initiation: Selegiline (Eldepryl) is another commonly used therapeutic. This product is an MAO-B inhibitor that limits the breakdown of both naturally occurring dopamine and dopamine formed from levodopa. Selegiline may delay the need for carbidopa-levodopa for about a year, and when taken with carbidopa-levodopa, may enhance the drug's effectiveness.

Parkinson's disease represents a multi-billion dollar market for the pharmaceutical sector: In 2006, the global sales of Parkinson's disease therapeutics were $3.1bn up by 11% from $2.5bn in 2005. Revenues of approved Parkinson's disease drugs across the major markets (US, Japan, France, Germany, Italy, Spain and the UK) totaled over $2.2bn in 2006, with revenues expected to exceed $4.6bn by 2012.

While it may seem distasteful to some talking about a disease as distressing as Parkinson's in terms of dollars, the size of the Parkinson's disease market is driving pharmaceutical activity which will hopefully improve options available to patients. We are currently seeing a climate of change in this market. A number of key drugs are approaching the end of their patent life while other new products are about to enter the market.

The future of Parkinson's disease: The leading therapeutics expected to change the Parkinson's disease market dynamics will include GSK's Requip Once-daily ER, UCB-Schwarz's Neupro and Teva/Lundbeck’s Azilect. Requip ER received an approvable letter from the FDA in Dec. 2007, while at about the same time UCB filed for Neupro. Other key compounds predicted for success include Kyowa Hakko’s Istradefylline, Merck-Serono/Newron’s Safinamide.

The new wave of Gene/cell Therapy compounds that have revealed positive initial clinical data, thus Neurotrophic growth factors (NGF), either to be injected directly into the brain are also tipped for potential market success. Ceregene’s Neuturine, Neurologix’ GAD (glutamic acid decarboxylase) amongst other similar drugs, will add to the present Parkinson's disease therapeutics that will expand revenue growth in the long-term.

More information on Parkinson's disease: LeadDiscovery currently lists over twenty in depth reports on various aspects of Parkinson's Disease (click here) plus over 200 journal articles (click here). To keep track of all activity in the Parkinson's Disease arena subscribe to DailyUpdates-Neurodegenerative Diseases [see todays edition here]

The Return of Drug Discovery

The more observant amongst you will notice that this is the first offering from Advances in Drug Discovery for a while.....in fact one year. This is not to say that there has been a lack of advances over the past 12 months. Quite the opposite and our silence has been due to the efforts that we have been placing on redesigning our main site, LeadDiscovery to better cover drug discovery.

Just a few words on what we have been up to before we continue from where we stopped this time last year.

DailyUpdates, our alert service now highlights key research and breaking news across 12 different therapeutics channels. The service is now a key intelligence tool across the pharmasphere. DailyUpdates is now supported by a monthly service, UpdatesPlus which takes a deep dive into R&D activity providing detailed analysis on selected indications or drug classes. Our portfolio of PharmaReports, in depth pharmaceutical market research and pipeline analysis reports, has expanded with over 1,000 reports now on offer. All in all we now offer insight into drug discovery at increasing levels of detail....so if you need to track a particular area of drug discovery let us help you, we can!

Anyway enough of us and onto the blog.

Todays edition of DailyUpdates covers nearly 50 key journal articles published over the past couple of weeks, a selection of trials and all the most important news. One of the journal articles that we would like to highlight here looks at the therapeutic potential of AT-101 which is featured in a paper highlighted on DailyUpdates-Oncology.

Cottoning onto apoptosis...

Ascenta Therapeutics' AT-101 is an enantiomer of gossypol, a natural product of cotton. The molecule is an orally active inhibitor of the Bcl-2 family of anti-apoptotic proteins and is in Phase 2 cancer trials in a number of oncology indications.

Apoptosis, or programmed cell death represents a pathway targeted by multiple oncology therapeutic candidates. The Bcl-2 proteins (Bcl-2 stands for B-cell lymphoma) comprise the best known anti-apoptotic group. Proteins from this family are frequently over-expressed in cancer making the cells resistant to death signaled by natural or therapeutic stimuli. There are at least five well characterized members of the Bcl-2 family: those most implicated in cancer progression and resistance to conventional therapies are Bcl-2, Bcl-X_L and Mcl-1. Over-expression of anti-apoptotic members of the Bcl-2 family are observed in the majority of Non-Hodgkin's lymphomas (NHLs) , contributing to intrinsic and acquired drug resistance. Since AT-101, inhibits each of these proteins there is strong proof of concept to support the development of AT-101 as a treatment of NHL.

NHL is the most common hematological malignancy and is comprised of around 30 different disease subtypes. Each of these present with a distinct set histological, genetic and clinical characteristics. Treatment options in NHL include chemotherapy, targeted therapies, stem cell transplantation and radiotherapy (see our recent feature Non-Hodgkin's Lymphoma - Is there room to emulate Rituxan's success?)

Rituxan-based regimens constitute the mainstay of first-line treatment options in several NHL subtypes. There is however a lack of consensus over the treatment of relapsed and refractory disease in most NHL subtypes. Refractory patients are poorly served by currently available treatment options. Consequantly the NHL late-phase pipeline is relatively active, with 10 Phase IIII drugs and 46 Phase II drugs.

In their upcoming paper in the journal Blood, Paolluzi et al characterize AT-101, one of these phase II candidates in B cell lymphoma. The IC50 for AT-101 was reported to be between 1 and 10 microM for a diverse panel of B-cell lymphomas. In a mouse model of drug resistant B-cell lymphoma, 35 mg/kg/day of AT-101 was safe and efficacious. The addition of AT-101 to cyclophosphamide and rituximab in a schedule-dependent manner enhanced the efficacy of the conventional therapy.

These data support the open-label, phase II trial of 52 NHL patients comparing rituximab with AT-101 and rituximab which commenced in the US in 2006.

LeadDiscovery currently featured 24 market research reports analyzing various aspects of NHL (click here for listing) and nearly 300 journal article selected for their importance to drug discovery (click here for listing). Interested readers can view our entire oncology portfolio here

Advances in the treatment of urge incontinence...Novel Approaches to Ventricular Fibrilation

Todays Headlines from across the DailyUpdates network

• Breaking News (from DailyUpdates-Genitourinary Tract Disorders): Advances in the treatment of urge incontinence: BioXell’s lead molecule, Elocalcitol, is a vitamin D3 analogue that is able to prevent proliferation of both prostate and bladder tissue induced by various growth factors. Elocalcitol entered Phase IIa evaluation for the treatment of BPH in April 2003 and was found to arrest prostate growth in 92% of patients. A Phase IIb trial is currently being conducted. One of the problems associated with BPH is overactive bladder, a symptom that results from bladder hypertrophy. Thus Elocalcitol represents a promising treatment for BPH as it has the potential to reduce both prostate growth and resultant bladder hypertrophy. As well as being caused by BPH, overactive bladder can also result from the aging process or various neurological conditions and the potential market for Elocalcitol may cross multiple subtypes of overactive bladder. This market is large with 68 million people being diagnosed in the 7 principal pharmaceutical markets in 2005 (see our recent feature Dry Overactive Bladder). A segment of this patient group go on to suffer Urge Urinary Incontinence which produces a greater loss of quality of life and incurs greater costs. Over $1 billion spent on drug treatments for overactive bladder although the main approach to treating the condition involves anti-muscarinic agents despite associated tolerability issues which limit compliance. Today’s featured press release from BioXell announces plans to proceed with a Phase IIb trial of Elocalcitol in overactive bladder. The new study follows the successful completion of a Phase IIa trial of Elocalcitol in 114 women with OAB, announced in May [Source:BioXell]

Featured Journal Article (from DailyUpdates-Cardiovascular Disease): Novel Approaches to Ventricular Fibrilation: Ventricular fibrillation causes more than 70% of out-of-hospital cardiac arrests and is responsible for 220,000 deaths each year in the US . Our recent report Ventricular & Atrial Fibrillation report includes a detailed analysis of the causes and current treatments of this arrhythmia. The primary objectives in ventricular fibrillation patients are to restore sinus rhythm rapidly and to reduce the chance of future episodes. Electrical defibrillation remains the cornerstone in acute treatment of ventricular fibrillation. The report discusses the potassium channel, Kir6.2 and the gap junction, connexin43 as molecular targets of future pharmacological therapeutics. The peptide rotigaptide (ZP123) targets the latter by increasing junction permeability and has recently been advanced into phase 2 trials by Wyeth following its in licensing from Zealand Pharma. Today’s featured journal article reports mechanistic data for rotigaptide and in particular demonstrates that it suppressed dephosphorylation of connexin43 Ser297 and Ser368 following ischemia. These data suggest that small molecule phosphatase inhibitors could offer alternate approaches to increasing connexin43 gap junction permeability thereby offering new approaches to cardiac arrhythmia J Mol Cell Cardiol. 2006 Jun;40(6):790-8. Epub 2006 May 5.

Breakthroughs in cardiovascular diseases

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Cardiovascular Diseases): Promising approach to acute limb ischemia As highlighted in our recent feature Acute Limb Ischemia (ALI) this condition is associated with high mortality especially in individuals with diabetes. Treatment options are limited and amputation is unfortunately the primary clinical approach to patients presenting with ALI. More conservative approaches represent a clearly unmet area, especially since hemorrhage represents a real risk in ALI patients treated with thrombolytics. Moreover, streptase (which is no longer available) was the only approved agent for the use in the periphery. A number of next generation thrombolytics are however under development in an attempt to reduce the risk of hemorrhage. The number of patients with ALI is difficult to determine with the commonly quoted figure of 40,000 in the US being very conservative; the ALI market thus represents a lucrative and largely under-exploited area. Today’s featured study represents one novel candidate approach to ALI. Kusumanto and colleagues report that intramuscular administration of phVEGF(165) (vascular endothelial growth factor gene-carrying plasmid) improved hemodynamic performance and reduced skin ulcers and pain in diabetic patients with ALI. Although the primary end-point of reduced amputation was not met, larger studies are warranted especially given the lack of adverse effects Hum Gene Ther. 2006 May 2; [Epub ahead of print]

Featured News Item (from DailyUpdates-Cardiovascular Diseases): Cardiome reports promising data on atrial fibrillation candidate In April, 2006 we highlighted Cardiome Pharma's announcement that the company's co-development partner, Astellas Pharma, had submitted an NDA to the FDA seeking approval to market the intravenous formulation of RSD1235, an investigational new drug for the acute conversion of atrial fibrillation. LeadDiscovery's brand new report on emerging pharmacological approaches to atrial and ventricular fibrillation (click here) concludes that RSD1235 is one of the most promising new candidates for patients with atrial fibrillation. The NDA is based on a 5-year clinical development program for RSD1235. RSD1235 is also being investigated as a chronic-use oral drug for the maintenance of normal heart rhythm following termination of AF. Phase I data concerning this indication were released by Cardiome on May 5^th, 2006). A Phase 2a pilot study for oral RSD1235 was initiated in December 2005 and interim results from this study have now been released. The data show that RSD1235 is well-tolerated and give the first indications of efficacy. Just as important, during the 28 days of oral dosing, serious adverse events occurred at a similar rate in placebo and RSD1235 treated patients, while, contrasting with other antiarrhythmics no cases of drug-related Torsades de Pointes were observed [source: Cardiome]

Involvement of GSK-3 in inflammation...FDA approves the use of Symbicort as a maintenance treatment of asthma

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Immunology and Inflammatory Diseases): Involvement of GSK-3 in inflammation [Licensing Option] Glycogen synthase kinase-3 beta (GSK-3b) is a serine threonine kinase with a broad array of cellular targets, such as cytoskeletal proteins and transcription factors. Since the mid-1990s there has been a near exponential rise in the level of GSK-3 related research and the therapeutic potential of GSK-3 inhibitors has become a major area of pharmaceutical interest. Initial targets of GSK-3 inhibitors were metabolic disorder, neurodegenerative diseases and potential psychiatric conditions. Today’s featured research suggests a role for GSK-3b in the control of inflammation. Previous research has implicated GSK-3b in NFkappaB pathways which in turn regulate the expression of inflammatory genes. Now researchers from Dr Reddy’s Laboratories in the US have reported direct evidence to show that GSK-3b is a negative regulator of cytokine expression by endothelial cells. In vivo studies reported that transfection of animals with GSK-3b reduces inflammation suggesting a novel approach to various conditions; on the other hand it reveals potential risks for the development of GSK-3 inhibitors. This is particularly the case for candidates being developed for metabolic disease given the potential role of inflammation in cardiovascular aspects of diabetes [J Biol Chem. 2006 Apr 19; [Epub ahead of print] ]

Featured News Item (from DailyUpdates-Immunology and Inflammatory Diseases): FDA approves the use of Symbicort as a maintenance treatment of asthma Global asthma/COPD sales should grow to $23 billion by 2014, with inhaled corticosteroid/long-acting bronchodilator combinations set to be the leading class by value in 2014, followed by leukotriene antagonists, and anticholinergics (see our feature on Asthma and COPD). One of the most successful combinations is Symbicort, marketed by AstraZeneca, which provides the inhaled corticosteroid budesonide (Pulmicort) and the rapid and long-acting bronchodilator formoterol (Oxis) in a single dose adjustable inhaler (Turbuhaler). Symbicort is indicated for the maintenance treatment of asthma. Although it won initial approval in Sweden as long ago as 2000, FDA approval has, as announced in today’s featured press release, only just been granted. Even prior to US market entry, annual sales were in excess of $1 billion, largely due to European success. Approval from the FDA should lift sales of Symbicort considerably although AstraZeneca does not plan to launch Symbicort in the US until mid 2007. AstraZeneca has also filed for European approval of Symbicort for the maintenance and acute symptomologic relief (SMART) of asthma. It is not clear whether AstraZeneca’s delay in launching Symbicort in the US is related to this European filing [source: AstraZeneca]

Johns Hopkins researchers identify candidate treatments of malaria and cervical cancer...A further fast track designation for Nexavar

Todays Headlines from across the DailyUpdates network

Featured Journal Article (from DailyUpdates-Infectious Diseases): Johns Hopkins researchers identify candidate treatments of malaria and cervical cancer [Licensing Option] Each year an estimated 300 to 500 million clinical cases of malaria occur, making it one of the most common infectious diseases worldwide. Malaria can cause high morbidity and mortality and indeed it is the cause of 1.5 to 2.0 million deaths/year. The economic burden of malaria is high, costing African healthcare systems as much as $0.5 billion each year. The emergence of drug resistant strains of malaria is significant and is driving the development of novel anti-malarials. Today’s featured research focuses on efforts from Dr Gary Posner’s lab at The Johns Hopkins University. This group has identified artemisinin derivatives with up to 37 fold greater efficacy than sodium artesunate, another derivative of artemisinin which is a component of current anti-malarials. Of interest, other artemisinin derivatives have been identified by Dr Posner’s group as candidate treatments of cervical cancer. This malignancy is diagnosed in about 13,000 American women each year. Although it is hoped that vaccines against HPV, the cause of cervical cancer, will eventually greatly reduce this incidence there will be a need for effective treatments of the disease for the foreseeable future [J Med Chem. 2006 May 4;49(9):2731-4]

Featured News Item (from DailyUpdates-Oncology): A further fast track designation for Nexavar We recently highlighted a press release from Bayer/Onyx announcing that they have received a positive opinion from the CHMP for Nexavar to be used in patients with advanced renal cell carcinoma. This followed approval by the FDA in December 2005 and in March 2006 in Switzerland . Nexavar has been shown to double progression-free survival in patients with advanced renal cell carcinoma. Nexavar is also being evaluated in Phase III clinical trials for the treatment of hepatocellular carcinoma and was granted Fast Track designation for this disease in June 2006. Nexavar is also being evaluated in a Phase III clinical trial for non-small cell lung cancer. Today’s highlighted release announces that Nexavar has now been granted Fast Track designation by the FDA for the treatment of advanced melanoma. Cancer of the skin (nonmelanoma and melanoma skin cancers combined) is the most common type of cancer, accounting for more than 50% of all cancers. Melanoma accounts for about 4% of skin cancer cases but causes about 79% of skin cancer deaths [source: Onyx]