http://www.prous.com Prous Science is a leading multiple-media publishing and information services company in the health and pharmaceutical sciences. Prous Science (c). Created of RSS by Jesus Moya. http://www.prous.com/ http://www.prous.com/images/design/prousscience5.gif http://www.prous.com/molecules/default.asp?ID=174 <p align="center"><img src="http://www.prous.com/images/moleculas/322926.gif"></p><P>Deposition of amyloid beta (Abeta) peptide into plaques is one of the two hallmark features of Alzheimer's disease. These plaques, typically concentrated in the spaces between nerve cells in the brain parenchyma and cerebral blood vessel walls, are thought to impede nerve cell function and promote neuronal degeneration in Alzheimer's disease brains. According to current thinking, AD etiology is explained by the amyloid cascade hypothesis, whereby overproduction of Abeta protein, or alternatively the failure to clear this protein, leads to the accumulation of amyloid deposits and contributes to the formation of neurofibrillary tangles. These lesions are associated with neuronal cell death, which manifests as loss of memory. Thus strategies to prevent the formation, accumulation or cytotoxic effects of Abeta are being actively pursued. Several potential interventions have been proposed to delay the onset or prevent the appearance of Alzheimer's disease, including Abeta production inhibitors (beta- and gamma-secretase inhibitors, statins, etc.); Abeta aggregation inhibitors; Abeta deposit-dissolving agents; and immunization with Abeta peptide. Furthermore, antiinflammatory therapies and metal chelating agents may minimize the brain's reaction to Abeta (Integrity<SUP>&reg;</SUP> Disease Briefings: <I>Alzheimer’s Disease</I>). </P> <P>In the spring of 2008, Lilly initiated its first phase III clinical trial of <B>semagacestat</B> (LY-450139) for the treatment of mild to moderate Alzheimer's disease. Semagacestat is being tested to see if it can slow the progression associated with Alzheimer's disease by inhibiting gamma-secretase, an enzyme that contributes to the formation of amyloid beta. The trial, called IDENTITY, is a randomized, double-blind, placebo-controlled trial that will be conducted in the U.S. and 21 additional countries and will evaluate 1,500 patients for 21 months. An open-label extension will be available to all participants completing the study. Patients who are taking currently available symptomatic treatments for Alzheimer's disease can continue treatment during their participation in IDENTITY. Because the IDENTITY study also incorporates a randomized delayed start design, even those subjects initially assigned to the placebo arm of the study will be started on active semagacestat treatment sometime before the end of the 21-month study period. Both the subjects and investigators will be blinded to the exact timing of this delayed start of study drug administration (ClinicalTrials.gov NCT00594568). Semagacestat was originally codeveloped by Lilly and Elan. </P> http://www.prous.com/molecules/default.asp?ID=173 <p align="center"><img src="http://www.prous.com/images/moleculas/313630.gif"></p><P>Thrombopoietin (TPO) is a glycoprotein hormone produced primarily by the liver that activates megakaryocytes in the bone marrow, causing them to differentiate and fragment into platelets. Under normal circumstances, the bloodstream platelet counts range from 150,000 to 400,000/mcl. However, under conditions of thrombocytopenia, platelet counts may drop below 50,000/mcl. Under these circumstances, patients are predisposed to bleeding, particularly at mucous membranes, and in some cases bleeding may become severe enough to require treatment.</P> <P>Thrombocytopenia is commonly associated with cancer chemotherapy and a number of other conditions, including AIDS, myelodysplastic syndrome, idiopathic thrombocytopenic purpura and chronic liver disease. The only treatment currently available for severe thrombocytopenia is platelet transfusion, but the known limitations and risks of this therapy have spurred investigation into novel methods of stimulating platelet production.</P> <P>A small-molecule, nonpeptide TPO agonist would be expected to offer several advantages over other therapies in terms of safety, cost and ease of administration. <B>Eltrombopag</B> (SB-497115, Promacta&reg;) an orally available small molecule that has been shown to activate the human TPO receptor, resulting in activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signal transduction pathways to stimulate the proliferation and differentiation of megakaryocytes. Activity has been demonstrated in vitro in human bone marrow assays and in clinical trials.</P> <P>Last year, results were published from a phase II study that evaluated 118 patients with chronic ITP and low platelet levels (&lt; 30,000/mcl). The results showed a statistically significant increase in the number of patients achieving a platelet count of 50,000/mcl or higher and decreased bleeding following eltrombopag doses of &gt; 50 mg over six weeks. There was no increased incidence of adverse events compared to placebo across the 30 mg, 50 mg or 75 mg eltrombopag arms. All seven patients who received the study drug and bled were nonresponders (Bussel, J.B. et al., Lancet 2007, 357(22): 2237-47).</P> <P>Product developer GlaxoSmithKline has filed for approval in the U.S. of eltrombopag as a once-daily, oral agent for the short- and long-term treatment of adult patients with previously treated chronic idiopathic thrombocytopenic purpura. The FDA has granted the product priority review status. The agency's decision is expected in the second quarter; if approved, eltrombopag would be the first treatment of its type to be approved for this indication. Eltrombopag is also phase III clinical studies for the treatment of thrombocytopenia in patients with hepatitis C infection.</P> http://www.prous.com/molecules/default.asp?ID=172 <p align="center"><img src="http://www.prous.com/images/moleculas/349654.gif"></p><P>Cathepsin K is a cysteine protease that is selectively and highly expressed by osteoclasts and secreted into the extracellular compartment, where it cleaves important bone matrix proteins, acting as the principal effector of bone degradation during the process of bone resorption. Activated cathepsin K degrades various bone matrix components including type I collagen, osteopontin and osteonectin. It is an attractive target for modulation in osteoporosis and other disorders caused by excessive bone resorption, because while it is expressed at high levels in bone, it is present at extremely low levels in the heart, liver, lung and other tissues. At the present time several cathepsin K inhibitors are under active development for the treatment of osteoporosis, including Merck & Co.’s <B>odanacatib</B> (formerly MK-0822), which has been selected as the Molecule of the Month. </P> <P>In a phase IIb study reported at last year’s meeting of the American Society of Bone and Mineral Research, odanacatib dose-dependently improved bone mineral density (BMD) in postmenopausal women with low BMD. The study included 399 women who were randomized in double-blind fashion to placebo or odanacatib 3, 10, 25 or 50 mg p.o. once weekly for 12 months. While the lowest odanacatib dose had no effect on BMD, the 10-, 25- and 50-mg doses were associated with dose-related increases in BMD at the lumbar spine, total hip, femoral neck and hip trochanter. The 50-mg dose significantly increased lumbar spine BMD at 12 months by 3.4&#37;, while this measure declined 0.1&#37; with placebo. Femoral neck BMD was also increased 2.5&#37; and the urinary N-telopeptide/creatinine ratio was reduced 58&#37; with the 50-mg odanacatib dose. Odanacatib was generally safe and well tolerated, with similar discontinuation rates due to adverse events in the active treatment and placebo groups (Bone, H.G. et al. J Bone Miner Res [29th Annu Meet Am Soc Bone Miner Res (ASBMR) (Sept 16-19, Honolulu) 2007] 2007, 22(Suppl. 1): Abst 1128). </P> <P>Based on these and other positive findings, Merck has begun enrolling patients in a phase III trial to evaluate odanacatib in postmenopausal women. The three-year study will determine the incidence of radiographic spine fractures and fractures at other body sites in patients taking odanacatib compared to placebo, as well as the drug’s effects on bone mineral density over the three-year study period (ClinicalTrials.gov identifier NCT00529373). In addition, several ongoing phase II trials are assessing the cathepsin K inhibitor for the treatment of osteoarthritis in the knee, arthritis and cancer, specifically for the treatment of women with breast cancer and metastatic bone disease. Banyu is developing the compound for the treatment of osteoporosis in Japan.</P> http://www.prous.com/molecules/default.asp?ID=171 <P>Cryopyrin-Associated Periodic Syndromes (CAPS) are a recently identified group of rare, inherited auto-inflammatory disorders characterized by life-long, recurrent symptoms of rash, fever/chills, joint pain, eye redness/pain and fatigue. Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to cooling temperatures, stress, exercise or other unknown stimuli. Three related conditions fall under the classification of CAPS: Familial Cold Auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Neonatal-Onset Multisystem Inflammatory Disease (NOMID). The incidence of CAPS has been reported to be approximately 1 in 1,000,000 people in the United States.</P> <P>CAPS are generally caused by mutations in the <I>NLRP-3</I> (previously known as <I>CIAS1</I>) gene and resultant alterations in the protein, cryopyrin, which it encodes. Cryopyrin, active in circulating, infection-fighting, white blood cells, controls the production of a protein called interleukin-1 (IL-1). As part of the body's infection-fighting defense system, IL-1 circulates throughout the body and can trigger inflammatory reactions when it binds to inflammatory cells. Researchers have found that alterations in the cryopyrin protein lead to over-production of IL-1, resulting in an inflammatory response and the symptoms of CAPS. Most, but not all, patients with CAPS have the <I>NLRP-3</I> gene mutation.</P> <P>Rilonacept, a targeted inhibitor of IL-1 discovered and developed by Regeneron, has been shown throughout its clinical development program to improve overall CAPS symptom scores. Last month at the AAAAI meeting in Philadelphia, results were reported from a 24-week extension of a 24-week study. Administered to patients with cryopyrin-associated periodic syndromes, including FCAS and MWS, rilonacept treatment was associated with sustained improvement in signs and symptoms. Of 47 patients initially treated with placebo or rilonacept 160 mg s.c. weekly, 44 entered the open-label extension study. The percentages of patients with at least 30&#37;, 50&#37; and 75&#37; improvement in key symptom scores at week 6 were 96&#37;, 87&#37; and 70&#37;, respectively, with rilonacept and 29&#37;, 8&#37; and 0&#37;, respectively, with placebo. At week 48, these percentages were 93&#37;, 91&#37; and 68&#37;, respectively, for rilonacept-treated patients receiving the treatment for 33-48 weeks. Key symptoms included rash, fever/chills, joint pain, eye redness/pain and fatigue. Large reductions in C-reactive protein and serum amyloid A were seen with rilonacept treatment at week 6 (92&#37; and 94&#37;, respectively) and after 33-48 weeks (77&#37; and 84&#37;, respectively) (Hoffman, H.M. et al. Annu Meet Am Acad Allergy Asthma Immunol (March 14-18, Philadelphia) 2008, Abst 669).</P> <P>In February the U.S. FDA approved rilonacept (Arcalyst&trade;) for the treatment of CAPS, including FCAS and MWS, in adults and children aged 12 years and older. The drug has not been evaluated in patients with NOMID. The product, which has orphan drug status in the U.S. for this indication, was launched in late March.</P> http://www.prous.com/molecules/default.asp?ID=169 <P>Overexpression of proinflammatory cytokines --especially IFN-gamma, TNF-alpha, IL-2, IL-6, IL-8, IL-12 and IL-23-- at the systemic and cutaneous level has been established in the context of psoriasis and is believed to underlie the initiation, maintenance and recurrence of skin lesions. Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) comprised of two independently regulated protein subunits, p35 and p40. The well-documented biological functions of IL-12 are the induction of IFN-gamma expression from T-cells and natural killer (NK) cells, and the differentiation of naïve T-cells to a Th1 cell type. In addition, the p40 subunit of IL-12 can dimerize with a p19 subunit and form IL-23, a more recently discovered member of the IL-12 family that also promotes a Th1 response but has distinct functions from IL-12. IL-23 is required for the generation of effector memory T-cells and IL-17-producing T-cells (Th17), which play a significant role in the inflammatory response (<A HREF="http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1158296&p_IsPs=N"><U>Wada, Y., Drugs Fut 2008, 33(1): 49</U></A>). </P> <P><B>Ustekinumab</B> (formerly CNTO-1275) is a human monoclonal antibody targeting IL-12 and IL-23. It has recently been shown that ustekinumab downregulates type 1 cytokines, chemokines and IL-12/IL-23 in psoriatic lesions of treated patients. Phase III trial results indicate that ustekinumab is effective with infrequent administration in patients with psoriasis and that efficacy is maintained with long-term treatment. In the PHOENIX 1 study, 766 patients were randomized to placebo or s.c. ustekinumab given in two 45- or 90-mg doses 4 weeks apart followed by 45 or 90 mg every 12 weeks. Placebo patients crossed over to ustekinumab 45 or 90 mg at weeks 12 and 16 and were than treated every 12 weeks. At week 12, 67&#37; and 60&#37; of patients given ustekinumab 45 and 90 mg, respectively, achieved the primary endpoint of an improvement of at least 75&#37; in Psoriasis Area and Severity Index (PASI 75) scores. A dose response was seen after week 12 with a peak response at week 24, with 76&#37; and 85&#37; of the ustekinumab 45 and 90 mg groups, respectively, achieving a PASI 75 response. Ustekinumab was generally well tolerated, with 57&#37; and 51&#37; of the ustekinumab 45 and 90 mg groups, respectively, experiencing at least one adverse event compared to 48&#37; of the placebo group (Papp, K. et al., J Am Acad Dermatol 2008, 58(2, Suppl. 2): Abst P2621). In this study, patients responding to ustekinumab at week 40 were randomized to either continue treatment or switch to placebo. At week 52, 87&#37; and 91&#37; of patients receiving ustekinumab 45 and 90 mg, respectively, maintained a PASI 75 response, compared to 64&#37; and 62&#37; of placebo-treated patients. Long-term maintenance therapy was generally well tolerated, with 46&#37; and 49&#37; of patients in the 45 and 90 mg dose groups, respectively, experiencing at least one adverse event after randomization at week 40, compared to 56&#37; and 48&#37; of patients switched to placebo (Gordon, K.B. et al., J Am Acad Dermatol 2008, 58(2, Suppl. 2): Abst P2620). </P> <P>Centocor and Jassen-Cilag have filed for regulatory approval of ustekinumab in the U.S. and European Union, respectively, for the subcutaneous treatment of adult patients with chronic moderate to severe plaque psoriasis. Medarex, originator of the therapeutic agent, is conducting phase III trials for the treatment of severe plaque-type psoriasis and Centocor is conducting additional phase II trials in patients with psoriatic arthritis. </P> http://www.prous.com/molecules/default.asp?ID=168 <p align="center"><img src="http://www.prous.com/images/moleculas/313738.gif"></p><P>Despite the availability of several approved drugs for the treatment of human immunodeficiency virus (HIV) infection, the limited effectiveness of current antiretroviral regimens, mainly due to the emergence of resistance, makes the development of new agents necessary. Several novel compounds are being added to existing classes, but the discovery and development of newer classes of antiretroviral drugs, such as HIV entry inhibitors, represents a significant advance in the treatment of AIDS and HIV. </P> <P>HIV enters the host cell by a sequential process that requires engagement with CD4 followed by binding to a coreceptor: either the chemokine CCR5 receptor (R5 strains) or CXCR4 (RX strains). The chemokine CCR5 receptor is a G-protein-coupled, 7-transmembrane receptor expressed on monocytes, macrophages, T cells and B cells that binds the CC chemokines MIP-1-alpha, MIP-1-beta and RANTES with high affinity. It also binds viral MIP-2 with high affinity and has been shown to bind cyclophilin-18 and histidyl-tRNA synthetase. CCR5 acts as a coreceptor with CD4 for HIV-1 infection and functions as a fusion cofactor for macrophage-tropic and T-cell line-tropic isolates of HIV-1. In general, during the early stages of HIV infection, viral isolates use CCR5 for viral entry, while later isolates use CXCR4. Antagonism of this receptor may therefore be effective in the prevention and treatment of HIV infection. </P> <P><B>Maraviroc</B> (<I>Selzentry</I>&trade;; Pfizer), the first member of the CCR5 antagonist class to cross the finish line, received accelerated approval from the U.S. FDA last August and was launched for the first time in September 2007. The drug acts by blocking the CCR5 coreceptor, thereby blocking viral entry into T cells. It is indicated for use in combination antiretroviral treatment of adults infected with CCR5-tropic HIV-1, evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The FDA approval was based on 24-week data from the ongoing double-blind, controlled MOTIVATE clinical trials, in which approximately twice as many patients receiving maraviroc plus optimized background therapy achieved undetectable viral load at 24 weeks compared to those on optimized background therapy alone. In September, Pfizer presented 48-week data supporting these initial findings, and announced the commercial availability of maraviroc in the U.S. Pfizer has also filed for regulatory approval of maraviroc in Europe, where it will be known as <I>Celsentri</I>, and has received a positive opinion from the CHMP. </P> http://www.prous.com/molecules/default.asp?ID=167 <p align="center"><img src="http://www.prous.com/images/moleculas/390240.gif"></p><P>Obatoclax mesylate (GX15-070) is a small-molecule indole bipyrrole drug compound and pan-Bcl-2 family inhibitor being developed at Gemin X Biotechnologies for the treatment of cancer. Recently published studies have confirmed the mechanism of action of the compound, demonstrating that it specifically disrupts the survival of cancer cells as a result of inhibiting the Bcl-2 pro-survival protein Mcl-1. Elevated expression of members of the Bcl-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells, and obatoclax overcomes Bcl-2 pro-survival proteins' resistance to the pro-apoptotic proteins BAX and BAK. The anti-apoptotic protein Mcl-1 plays a particularly central role in conferring cancer cell resistance in certain instances, and obatoclax potently interferes with the direct interaction between Mcl-1 and BAK in the intact mitochondrial outer membrane and inhibited the association between Mcl-1 and BAK in intact cells. It is thought that Mcl-1 regulates BAK within the mitochondrial outer membrane (Nguyen, M. et al. Proc Natl Acad Sci USA 2007, 104(49): 19512).</P> <P>During the recent annual meeting of the American Society of Hematology, results were presented from several preclinical and clinical studies evaluating obatoclax. Obatoclax inhibited cell proliferation and induced apoptosis in drug-resistant non-Hodgkin's B-cell lymphoma cell lines, including those resistant to rituximab. No cytotoxicity was seen with obatoclax in human peripheral blood leukocytes from different donors (Martinez-Paniagua, M.A. et al., Abst 1402). Experiments in chronic lymphocytic leukemia cells showed that increased levels of phosphorylated Bcl-2 reduced obatoclax cytotoxic activity. The synergistic activity seen with obatoclax and bortezomib was also regulated by Bcl-2 phosphorylation, and combination with ERK inhibitors showed potential in increasing the activity of the compound (Galan, P.P. et al., Abst 3464). </P> <P>A phase I study was conducted in patients with relapsed or refractory mantle cell lymphoma to evaluate the combination of obatoclax and bortezomib. The dosage selected for further assessment was 45 mg/1.3 mg/m2, administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle which displayed acceptable tolerability. Evidence of activity was seen (Goy, A. et al., Abst 2569). Prolonged infusions of obatoclax were assessed in patients with hematological malignancies enrolled in a phase I trial, with 21 patients receiving obatoclax 20-28 mg/m2/day weekly or 20 mg/m2/day for 2, 3 or 4 consecutive days every 2-3 weeks. Multiple-day infusions were well tolerated. A patient with acute myelogenous leukemia achieved a cytogenetic complete response with complete hematological recovery and transfusion independence on day 9 after starting weekly obatoclax infusions (Schimmer, A.D., Abst 892). </P> <P>Obatoclax is currently being evaluated in a phase II trial in patients with chronic idiopathic myelofibrosis (CIMF). Patients are given a dose of 60 mg by 24-hour infusion every 2 weeks. In 14 patients with data available after administration of 102 cycles, grade 3 adverse events included peripheral edema, dyspnea, fatigue, diarrhea and chest pain. Plasma obatoclax concentrations appeared to reach steady state before the end of the infusion. Of 8 previously treated patients, 2 had a Clinical Improvement Response lasting 6 months with increases in hemoglobin and red blood cell transfusion independence while continuing chronic recombinant erythropoietin therapy to which they had not previously responded. Of 6 previously untreated patients, 3 were still on therapy with stable disease at the time results were reported (Verstovsek, S. et al., Abst 3553). </P> <P>Obatoclax is also undergoing phase II clinical evaluation for the treatment of Hodgkin's lymphoma, myelofibrosis with myeloid metaplasia, myelodysplasia and follicular lymphoma. Early clinical studies are also under way for the treatment of chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute myeloid leukemia, relapsed or refractory non-small cell lung cancer, relapsed or refractory mantle cell lymphoma and solid tumors. The NCI is conducting studies of obatoclax in combination with topotecan in patients with relapsed or refractory small cell lung cancer and solid tumors. Obatoclax was granted orphan drug designation by the FDA in 2004 for the CLL indication.</P> http://www.prous.com/molecules/default.asp?ID=166 <p align="center"><img src="http://www.prous.com/images/moleculas/343476.gif"></p><P>Synta Pharmaceuticals' <B>elesclomol</B> (STA-4783), a first-in-class small-molecule oxidative stress inducer, has been selected as the Molecule of the Month. Elesclomol induces an oxidative stress response in cancer cells by inducing heat shock protein 70 (Hsp70), thereby inducing apoptosis and enhancing the activity of certain anticancer agents such as paclitaxel. In October, Synta signed a global collaboration agreement with GlaxoSmithKline for the joint development and commercialization of elesclomol. Under the terms of the agreement, the companies will share responsibility for development and commercialization of elesclomol in the U.S. and GSK will have exclusive responsibility for development and commercialization of the product outside the U.S. In addition, Synta will also be eligible to receive potential milestone payments for events leading to approval of elesclomol in metastatic melanoma, and further development and regulatory milestones across various indications. Elesclomol was granted fast-track designation by the FDA in 2006 for the treatment of metastatic melanoma.</P> <P>In a double-blind, randomized, multicenter phase II trial reported last summer at ASCO, 81 patients with metastatic melanoma were randomized to receive paclitaxel (80 mg/m2) plus elesclomol (213 mg/m2) or paclitaxel alone for three weeks on a four-week schedule. Intent-to-treat analysis revealed a median progression-free survival (PFS) of 3.68 and 1.84 months, respectively, for the combination versus paclitaxel alone and a response rate of 15.1&#37; and 3.6&#37;, respectively. Chemotherapy-naive patients showed an even greater benefit on the combination, with a median PFS of 8.28 and 2.40 months, respectively, for the combination and paclitaxel alone. Moreover, several patients progressing on paclitaxel alone showed a delay in the time to progression when elesclomol was added. Adverse event rates were similar in both treatment groups, the most common events in the combination group being fatigue, alopecia, constipation, nausea, arthralgia, insomnia, diarrhea, anemia and hypoesthesia (O'Day, S. et al., 43rd Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2007: Abst 8528; Kirshner, J. et al. 43rd Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2007: Abst 14107).</P> <P>In mid-November, Synta announced that the first patients had been treated in the SYMMETRY(SM) (Synta Metastatic Melanoma Elesclomol Trial) trial, a global, pivotal phase III clinical trial to evaluate the safety and efficacy of elesclomol in patients with stage IV metastatic melanoma. Synta has also successfully completed the special protocol assessment process, reaching agreement with the FDA on the design, conduct and planned analyses of the trial. The trial is enrolling patients with stage IV metastatic melanoma who have not received prior chemotherapy but who may have already been treated with non-chemotherapeutic agents such as biologics. Approximately 630 patients will be enrolled in the blinded, randomized, controlled study, which will be conducted at approximately 150 centers worldwide. Patients will be randomized (1:1) to elesclomol (213 mg/m2) plus paclitaxel (80 mg/m2) or paclitaxel alone (80 mg/m2) and will receive three weekly treatments and one week without treatment per each four-week cycle. If tolerated, treatment will continue until disease progression. The control arm treatment, the combination arm treatment, the doses, the schedule and the primary endpoint of progression-free survival (PFS), are the same as in the above phase IIb trial. There are two planned analyses for the primary endpoint of PFS: an interim analysis to assess safety and non-futility will be conducted and reviewed by an independent data safety monitoring board, and the final analysis for PFS will be initiated when enrollment is close to completion. At the time of the final analysis for PFS, a first interim analysis will also be performed for overall survival (OS), a secondary endpoint. Following these, two additional analyses for OS are planned: a second interim analysis and a third and final OS analysis. Synta expects to complete the primary endpoint analysis by the end of 2008 and file an NDA with the FDA by the first half of 2009. </P> http://www.prous.com/molecules/default.asp?ID=165 <p align="center"><img src="http://www.prous.com/images/moleculas/356099.gif"></p><P>Sodium-dependent glucose transport proteins (SGLTs) play a key role in maintaining glucose homeostasis in the human body. SGLTs are found in the intestine (SGLT1) and the kidney (SGLT1 and SGLT2). Renal SGLT reabsorbs glucose from the renal filtrate, thus preventing loss of glucose in urine. Renal SGLTs are found in the pars convoluta of the nephron's proximal tubule. SGLTs use the energy from a positive sodium gradient to transport glucose across the membrane. SGLT2 has a 1:1 ratio of sodium-glucose transport. SGLT1 works similarly but has a 2:1 ratio of sodium-glucose transport. SGLT2 accounts for 98&#37; of renal glucose reabsorption, whereas SGLT1 accounts for the remaining 2&#37;. Transcellular glucose transport is facilitated by the basolateral membrane glucose transporters GLUT2 and GLUT1. Binding of glucose to one side provokes a conformational change that causes the release of glucose into the other side of the membrane. SGLT2 inhibitors are being developed as potential antidiabetic agents because of their ability to specifically reduce transcellular epithelial glucose reabsorption.</P> <P>Clinical studies of <B>dapagliflozin</B> (BMS-512148; Bristol-Myers Squibb/AstraZeneca), an inhibitor of the sodium-glucose cotransporter (SGLT2), were presented at the 2007 meeting of the European Association for the Study of Diabetes (EASD). Two studies of dapagliflozin in healthy subjects were reported. In one, 40 subjects received doses of 2.5, 10, 20, 50 or 100 mg p.o. o.d. or placebo for 14 days. Dapagliflozin was safe and well tolerated, with rash the most common adverse event. Maximal inhibition of renal glucose resorption was seen with doses of 20-100 mg (Brenner, E. et al. 43rd Eur Assoc Study Diabetes (EASD) Annu Meet (Sept 17-21, Amsterdam) 2007, Abst 0765). Single dapagliflozin doses of 2.5-500 mg or placebo were given to healthy fasted subjects (n = 64) in a second study, and the dapagliflozin doses were well tolerated. Administration of dapagliflozin 250 mg after a high-fat meal delayed the tmax but did not greatly affect the AUC (Li, L. et al. 43rd Eur Assoc Study Diabetes (EASD) Annu Meet (Sept 17-21, Amsterdam) 2007, Abst 0764).</P> <P>An exclusive animation depicting SGLT-2 as a target for the development of antidiabetic drugs has been published on Prous Science’s LifeSciChannel and in the Integrity&reg; Disease Briefings knowledge area, where it can be found in the “Diabetes” report. Dapagliflozin, the most advanced compound in this novel class of oral antidiabetic agents, is currently in phase III clinical testing for the treatment of type 2 diabetes. The drug was discovered by Bristol-Myers Squibb and has been licensed to AstraZeneca for development and commercialization. Two trials are currently recruiting participants: one in diabetic subjects not adequately controlled on metformin alone (NCT00528879) and the other in those not adequately controlled with diet and exercise alone (NCT00528372).</P> http://www.prous.com/molecules/default.asp?ID=164 <p align="center"><img src="http://www.prous.com/images/moleculas/306386.gif"></p><P><B>Sugammadex sodium</B>, a reversal agent used during general anesthesia, is the first selective relaxant binding agent (SRBA), a drug-specific cyclodextrin that is specifically designed to reverse the effects of the muscle relaxant rocuronium bromide (Esmeron<SUP>&reg;</SUP>/Zemuron<SUP>&reg;</SUP>) when the latter is used as a component of general anesthesia during surgical procedures. Current reversal agents can only be administered when muscle relaxation is starting to wear off naturally; however, sugammadex can achieve reversal following rocuronium bromide administration within three minutes, regardless of the depth of block. Furthermore, in studies to date, sugammadex has shown less adverse effects than the currently available agents. Sugammadex encapsulates the muscle relaxant and forms a very tight, water-soluble host-guest complex, removing the drug from its site of action and rendering it inactive. A chemically modified gamma-cyclodextrin compound, sugammadex alone does not have an appreciable activity in the body. </P> <P>Drug developer Organon has described safety and efficacy data obtained in more than 1,700 patients, including data from ten global phase III trials. In these studies, sugammadex has generally demonstrated the ability to reverse shallow and profound depths of rocuronium-induced neuromuscular blockade within three minutes, thereby enabling control of the onset and offset of skeletal muscle relaxation through the use of both drugs. In the pivotal phase III Aurora trial, reported last summer, sugammadex induced a 9-12 times faster reversal of neuromuscular blockade as compared to neostigmine, without evidence of postoperative residual curarization (PORC) or reoccurrence of muscle relaxation. The Aurora trial compared the efficacy of sugammadex and neostigmine for the reversal of shallow neuromuscular blockade induced by single or multiple doses of either rocuronium or vecuronium, another neuromuscular blocking agent. The international, randomized, multicenter, parallel-group trial was conducted at 13 European centers and enrolled 198 patients. In the trial sugammadex was administered at reappearance of T2 and achieved significantly faster recovery of the T4/T1 ratio to 0.9 compared with neostigmine. Median time to recovery was 1.4 minutes for sugammadex versus 17.6 minutes for neostigmine following rocuronium administration and 2.1 minutes versus 18.9 minutes respectively following vecuronium administration. There were no clinical events due to PORC or recurarization reported for either group. Data from three other phase III trials demonstrated that sugammadex was effective and well tolerated in pediatric patients, in patients with mild or moderate impaired renal function and in comparison with neostigmine-glycopyrrolate after cisatracurium. Based on data from these and other studies, Organon has filed for approval of sugammadex in the E.U. Filings are proceeding according to plan in Japan and the U.S.</P> http://www.prous.com/molecules/default.asp?ID=163 <p align="center"><img src="http://www.prous.com/images/moleculas/196024.gif"></p><P>The chemokine CXCR4 (SDF-1) antagonist <B>plerixafor hydrochloride</B> (AMD-3100, Mozobil&trade;) is in phase III clinical development at Genzyme, which acquired the product through its acquisition of AnorMED in late 2006. AnorMED had been developing plerixafor for the treatment of HIV, but discontinued the trials in 2001 due to abnormal cardiac activity and lack of efficacy. </P> <P>By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood, where they can be collected for use in stem cell transplant. The current standard of care for stimulating the mobilization of stem cells from the bone marrow is with granulocyte colony-stimulating factor (G-CSF). Plerixafor is being developed in combination G-CSF as a novel stem cell mobilization regimen in patients undergoing stem cell transplantation for the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). The trials are designed to evaluate the ability of plerixafor plus G-CSF to rapidly increase the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target and, as a result, reducing the number of apheresis sessions required for patients to collect a target number of peripheral blood stem cells. </P> <P>In July, Genzyme announced that it had successfully completed a first phase III trial of plerixafor in non-Hodgkin's lymphoma, and that the trial had met its primary and secondary endpoints. The randomized, double-blind, placebo-controlled trial examined the effectiveness of plerixafor in increasing the number of hematopoietic stem cells collected for a transplant in 298 patients undergoing a hematopoietic stem cell transplant (HSCT) for NHL at medical centers in the U.S. and Canada. The study compared the hematopoietic stem cell yields from patients treated with plerixafor plus G-CSF to patients treated with G-CSF in combination with placebo. In the primary efficacy endpoint, 59&#37; of patients treated with plerixafor/G-CSF achieved the target threshold for collection of at least 5 million CD34+ cells/kg from the peripheral blood with 4 or fewer days of apheresis sessions, compared with 20&#37; of patients in the G-CSF/placebo group. The three-fold increase was highly statistically significant in favor of the study drug. The 40&#37; absolute difference between the two treatment groups was nearly double the target that Genzyme had prospectively defined in the protocol for the study, which was reviewed by the FDA as part of the Special Protocol Assessment (SPA) process. In the secondary efficacy endpoint, nearly 87&#37; of patients treated with plerixafor/G-CSF achieved the minimum level of stem cells generally associated with a successful transplant in 4 or fewer days of apheresis sessions, compared with approximately 47&#37; in the placebo arm. The other secondary efficacy endpoints were supportive of these findings, including number of days needed to reach target ranges for stem cell mobilization, success of engraftment, number of days needed to engraft and durability of the engraftment for the first 100 days. </P> <P>A few weeks later, Genzyme announced similar positive results from a separate phase III trial comparing plerixafor/G-CSF to G-CSF/placebo for stem cell mobilization prior to autologous HSCT in patients with multiple myeloma. Similar to the NHL results above, plerixafor was shown to enable 72&#37; of patients to achieve target thresholds for stem cell collection (&ge; 6 million CD34+ cells/kg) from peripheral blood with two days or fewer of apheresis sessions, as compared to only 34&#37; of patients in the G-CSF/placebo group. The study's secondary outcomes were also met, showing a statistically significant result in favor of plerixafor in the number of patients reaching the target threshold within 4 days of apheresis, and the number of patients who reached at least 2 million cells collected in 4 days. Other secondary outcomes were also supportive, including success of engraftment, number of days needed for engraftment, and durability of engraftment for the first 100 days. The trial also robustly met the primary endpoint specified by EMEA, which is a composite of successful mobilization and engraftment. The study drug was well tolerated in both trials.</P> <P>Based on these results, Genzyme expects to file for U.S. and European approval in both the lymphoma and multiple myeloma indications in the first half of 2008. Plerixafor has been granted SPA and orphan drug status in the U.S. and the E.U., and the pivotal trials have undergone special protocol assessment by the FDA and protocol assistance by the EMEA. </P> http://www.prous.com/molecules/default.asp?ID=162 <p align="center"><img src="http://www.prous.com/images/moleculas/398997.gif"></p><P><B>Dimebolin hydrochloride</B> (Dimebon&trade;) is an orally-available, small-molecule agent that is in clinical testing for the treatment of Alzheimer's and Huntington's diseases-two progressive, devastating conditions with limited treatment options. Based on clinical and preclinical data generated to date, developer Medivation believes that dimebolin operates via a novel mechanism of action and may exert a neuroprotective effect in multiple areas of the central nervous system. Dimebolin appears to block a new target that involves mitochondrial pores, which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process. Dimebolin also blocks both cholinesterase and the NMDA receptor simultaneously. These two targets provide the mechanism of action for all FDA-approved drugs for Alzheimer's disease, although no marketed drug is known to have an effect on both pathways.</P> <P>In July, the Huntington Study Group (HSG) reported that recruitment of participating sites for the DIMOND phase II trial (ClinicalTrials.gov identifier: NCT00497159), which will evaluate dimebolin in subjects with mild to moderate Huntington's disease (HD), is currently in progress. The randomized, double-blind, placebo-controlled phase II trial will enroll up to 90 patients at some 15 research centers in the U.S. and U.K. It is designed to evaluate the safety and tolerability of dimebolin during three months of treatment, as well as its effects on cognition, motor signs and overall functioning of HD patients aged 18 years or older. Patient enrollment will begin during the summer of 2007. </P> <P>In June, the company reported that benefits of dimebolin hydrochloride over placebo in a double-blind, placebo-controlled phase II study in mild to moderate Alzheimer's disease (AD) were statistically significant on all five study endpoints at 12 months. In the multicenter, double-blind trial, 183 patients with mild to moderate AD were randomized to oral dimebolin (60 mg/day) or placebo for six months. Of these patients, 134 subsequently consented to continue treatment for up 12 months in their same treatment group. On the primary endpoint, the ADAS-cog, dimebolin caused an improvement over placebo of 6.9 points at one year. On the global function endpoint used in this study, the CIBIC-plus, dimebolin's benefit over placebo was 0.8 points at 12 months. Global function improved or remained stable in 69&#37; of treated Alzheimer's disease patients after one year of dimebolin therapy. Dimebolin produced an aggregate benefit over placebo in this study that was larger at 12 months than at six. After a year of treatment, dimebolin's benefit over placebo was greater than six-month levels on the ADAS-cog (6.9 points vs. 4.0 points), CIBIC-plus (0.8 points vs. 0.6 points), and ADCS-ADL (5.2 points vs. 2.9 points) scales; however, only the ADAS-cog difference reached statistical significance. Dimebolin's benefit over placebo on the other two endpoints (the Mini Mental State Exam, [MMSE] and the Neuropsychiatric Inventory [NPI]) at six months was maintained at one year. Dimebolin-treated patients experienced significantly fewer serious adverse events than placebo-treated patients (3.4&#37; vs. 11.7&#37;). The most frequent adverse events associated with treatment were dry mouth, depressed mood/depression and sweating. Six-month phase III studies of dimebolin in AD will begin next year.</P> <P>Dimebolin hydrochloride, which also acts as an antihistamine, is marketed in Russia by the Russian Academy of Sciences for the treatment of skin allergy and allergic rhinitis. <P> <P><FONT COLOR="Navy"><I>The information in this summary was derived from company sources and the Prous Science Integrity&reg; and is current as of July 16, 2007. For continuously updated information on dimebolin, including new bibliographical references, Disease Briefings, clinical trials, regulatory information, patents and more, consult Integrity&reg;.</I></FONT></P> http://www.prous.com/molecules/default.asp?ID=161 <p align="center"><img src="http://www.prous.com/images/moleculas/218793.gif"></p><P>The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to a family of phosphatidylinositol kinase-related kinases, which mediate cellular responses to stresses such as DNA damage and nutrient deprivation. mTOR acts as a target for the cell cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. mTOR plays a critical role in controlling cell growth, since it receives stimulatory signals from Ras and PI-3 kinase downstream from growth factors, as well as information on nutrient levels in the form of amino acid, glucose and oxygen availability. Its function is to integrate extracellular signals with amino acid availability and energy status of the cell and modulate translation rates of the proteins and other metabolic events accordingly. mTOR phosphorylates eIF4E binding proteins and the ribosomal protein S6 kinases to regulate protein translation rates, and its activity is closely associated with a 12-kDa immunophilin FK506-binding protein (FKBP12). mTOR inhibitors have been identified as promising agents for cancer prevention and/or therapy. </P> <P>The cell cycle inhibitor <B>temsirolimus</B> (CCI-779) works by specifically inhibiting mTOR-driven cell proliferation. Based on its promising anticancer activity, temsirolimus has been evaluated in a range of oncology indications including renal cell carcinoma, lymphoma, leukemia, sarcoma, glioblastoma, melanoma, non-small cell lung, ovarian, prostate, breast and endometrial cancers and more. In late May, the U.S. FDA approved temsirolimus for the treatment of renal cell carcinoma (RCC). The rapid approval of temsirolimus in the U.S. was facilitated by both fast-track and priority review status. Temsirolimus has orphan drug status in both the U.S. and E.U. for the renal cell carcinoma indication. </P> <P>In a three-arm, phase III trial of 626 patients with advanced RCC and poor prognosis who had received no prior systemic therapy, temsirolimus significantly increased median overall survival by 49&#37; compared to interferon alpha (10.9 months vs. 7.3 months). The mTOR inhibitor also was associated with a statistically significant improvement over interferon alpha in the secondary endpoint of progression-free survival (5.5 months vs. 3.1 months). The combination of temsirolimus and interferon alpha did not result in a significant increase in overall survival when compared with interferon alpha alone (Hudes, G. et al., New Engl J Med 2007, 356(22): 2271-81). </P> <P>Drug manufacturer Wyeth plans to launch temsirolimus (<I>Torisel</I>&trade;) in July. As part of a postmarketing commitment, Wyeth has agreed to submit two completed study reports and data sets: one on a thorough QT prolongation study and one on an ongoing hepatic impairment study. </P> <P><FONT COLOR="Navy"><I>The information in this summary was derived from Prous Science Integrity&reg; and is current as of June 26, 2007. For continuously updated information on temsirolimus, including new bibliographical references, clinical trials, regulatory information, patents and more, consult Integrity&reg;. </I></FONT></P> http://www.prous.com/molecules/default.asp?ID=160 <P>Paroxysmal nocturnal hemoglobinuria (PNH, also sometimes called Marchiafava-Micheli Syndrome) is a rare, incurable acquired blood disorder characterized by a decreased number of red blood cells (anemia) and the presence of blood in the urine (hemoglobinuria) and plasma (hemoglobinemia), which is most evident after sleeping. PNH is associated with a high risk of major thrombotic events, most commonly thrombosis of large intra-abdominal veins. Thrombosis is an important cause of mortality among PNH patients. The disease may arise in relation to aplastic anemia, and may progress to acute myelogenous leukemia. The prognosis for patients with PNH is bleak, and most patients do not survive more than ten years from the time of diagnosis. Prior to 2007, there were no drugs specifically approved for the indication of paroxysmal nocturnal hemoglobinuria.</P> <P><B>Eculizumab</B> (Soliris&trade;), developed by Alexion Pharmaceuticals, was approved and launched earlier this year in the U.S., becoming the first treatment ever for PNH, as well as the first ever marketed therapeutic with a novel mechanism of action: complement inhibition. Eculizumab is a recombinant humanized monoclonal antibody that blocks the complement cascade through binding to the terminal complement protein C5. The European Committee for Human Medicinal Products has also recommended the E.U. approval of the product. Eculizumab has orphan drug status in both the U.S. and the E.U.</P> <P>PNH is caused by an acquired mutation in a gene (<I>PIG-A</I>) encoding a protein essential for the synthesis of glycosylphosphatidylinositol (GPI), a plasma membrane lipid that allows the anchoring of several proteins to the cell surface. Patients with PNH produce hematopoietic clones with complete or partial deficiency of GPI-linked proteins such as CD55 and CD59, two proteins that protect cells from complement attacks. This lack of protection and the resulting susceptibility to complement-mediated cell destruction is the primary cause of the symptoms commonly found in PNH (i.e., intravascular hemolysis, venous thrombosis and hemoglobinuria). Eculizumab specifically targets this defect.</P> <P>Eculizumab proved to be a safe and effective therapy for PNH in three multinational clinical studies: TRIUMPH, a placebo-controlled 26 week phase III study involving 87 PNH patients; SHEPHERD, an open-label, 52-week phase III trial involving 97 PNH patients; and E05-001, a long-term extension study. These studies showed that the complement inhibitor reduced hemolysis in every treated patient. Hemolysis was dramatically reduced from a baseline LDH of 2,032 U/l to 239 U/l at week 26. The reductions in hemolysis occurred within one week of initiating treatment and were sustained for periods of up to 54 months with continued dosing of eculizumab. The reduction in hemolysis expands the number of circulating PNH cells, and thereby increases the hemoglobin level. Hemoglobin stabilization and the number of transfused packed red blood cell units, the pivotal study's coprimary endpoints, were both achieved; half of the eculizumab-treated patients achieved hemoglobin stabilization compared with none of the patients in the placebo group, and the median number of transfusions was reduced from 10 units/patient to 0 units/patient, respectively. Patients receiving eculizumab therapy reported less fatigue and improved health-related quality of life. There were fewer thrombotic events with the treatment than during the same period of time prior to treatment.</P> http://www.prous.com/molecules/default.asp?ID=159 <p align="center"><img src="http://www.prous.com/images/moleculas/162578.gif"></p><p><b>Paliperidone</b>, the active metabolite of the known atypical antipsychotic risperidone, was launched in the U.S. in 2007 for the treatment of schizophrenia. The product, known as Invega&trade;, was developed by Johnson &amp; Johnson based on Alza's OROS drug delivery system, which is designed to deliver paliperidone over a 24-hour period. </p> <p>Data from several studies adding detail to previously released clinical trial data on the effects of paliperidone extended-release tablets in schizophrenia were made available at the 11th International Congress on Schizophrenia Research, celebrated March 8-April 1, 2007 in Colorado Springs. Data pooled from three 52-week, open-label extension studies of paliperidone ER in 1,083 patients with acute schizophrenia, treatment-related adverse events occurred in 76&#37; of patients and were most often insomnia, headache, akathisia, anxiety and psychotic disorder. Long-term safety was consistent with results from short-term studies, and efficacy was maintained (Eerdekens, M. et al., Abst P2-290). Data from clinical studies was used to compare paliperidone to risperidone in an analysis conducted to fill the absence of a direct comparison. The reduction in PANSS total score was greater with paliperidone than with risperidone, and paliperidone was associated with lower rates of akathisia, restlessness, anxiety, insomnia, somnolence, dizziness and gastrointestinal disturbances (Schooler, N. et al., Abst P2-373). Patients who had been treated with risperidone were treated with fixed doses of paliperidone or placebo. Paliperidone was associated with a significant improvement in mean PANSS total score, mean PANSS factor change scores, mean PSP and CGI scores at endpoint (Canuso, C. et al., Abst P2-372). The efficacy of paliperidone was also investigated in 199 patients previously treated with olanzapine. The mean PANNS total score improved significantly with paliperidone as compared to placebo, and all mean PANSS factor change scores, PSP and CGI scores were significantly improved at endpoint with paliperidone (Dirks, B. et al., Abst P2-371).</p> <p>A regulatory application has been filed in the E.U. for the schizophrenia indication. Phase III trials are under way for the treatment of bipolar disorder and schizoaffective disorder. Paliperidone enters a market currently dominated by five antipsychotic drugs, which together reap worldwide sales of more than US $14 billion annually, according to Integrity&reg;. </p> http://www.prous.com/molecules/default.asp?ID=158 <p align="center"><img src="http://www.prous.com/images/moleculas/283279.gif"></p><P>Oral antiplatelet drugs form the cornerstone of treatment for patients with vascular disease, due to their demonstrated beneficial effects on reducing cardiovascular morbidity and mortality. AstraZeneca’s <b>ticagrelor</b> (formerly AZD-6140), the first reversible oral P2Y12 receptor antagonist, is being developed as an alternative to clopidogrel, currently a market leader among antiplatelet drugs. Ticagrelor is expected to be especially indicated for the treatment of the approximately 15-30&#37; of all atherosclerosis patients who do not respond to clopidogrel, as well as those patients who must undergo surgery and thus are not candidates for treatment with clopidogrel, which has long-acting and irreversible antiplatelet effects. </p> <p>Antiplatelet drugs such as clopidogrel and ticagrelor inhibit platelet activation by ADP, while leaving the final common platelet aggregation pathway, which is mediated by the fibrinogen receptor, intact. This provides the advantage of a wider therapeutic window between the desired inhibition of unwanted thrombosis and the undesirable clinical bleeding that occurs through less targeted inhibition. Unlike clopidogrel, ticagrelor is a non-thienopyridine that acts directly on the P2Y12 receptor, with a rapid onset of action of approximately 2 hours. Being a reversible antagonist, it also has a rapid offset of action of approximately 12 hours. Using a twice-daily dosing regimen, the DISPERSE and DISPERSE2 clinical studies have demonstrated more potent and consistent platelet aggregation inhibition as compared to clopidogrel. Some unwanted but self-limited side effects (dyspnea, bradycardic effect and increases in uric acid) have been observed that will require further evaluation in phase III trials. </p> <p>Ticagrelor is currently being evaluated in a randomized, double-blind, parallel-group, international phase III efficacy and safety study in comparison with clopidogrel for the prevention of vascular events in patients with non-ST or ST elevation acute coronary syndromes (ACS) (ClinicalTrials.gov identifier NCT00391872). </p> http://www.prous.com/molecules/default.asp?ID=157 <p align="center"><img src="http://www.prous.com/images/moleculas/377425.gif"></p><P>Attention deficit/hyperactivity disorder (ADHD; also known as attention deficit disorder or hyperkinetic disorder) is a complex neuropsychiatric and behavioral disorder characterized by inattentive, hyperactive and impulsive behavior. Although estimates vary widely, the Centers for Disease Control and Prevention (CDC) estimates that nearly 8&#37; of school-age children in the U.S. have ADHD, making this one of the most common behavioral and psychological disorders encountered in pediatric medicine.</P> <P>Psychostimulant drugs have been used in the treatment of attention deficit/hyperactivity disorder for more than 60 years. The most widely used and well studied psychostimulant is methylphenidate (<em>Ritalin</em>); other drugs in this class include dextroamphetamine and pemoline. Nine out of ten patients improve with psychostimulants. Through their predominantly dopaminergic mechanism of action, drugs in this class produce beneficial effects on the defining symptoms of ADHD (overactivity, attention span, impulsivity, self-control) and associated aggressiveness, although they may not correct all behavior problems. However, psychostimulants may be addictive to adolescents and adults if misused, and this concern has generated significant debate among individuals with ADHD and their families. These drugs are not considered to be addictive in young children; nonetheless, administration of stimulants in the U.S. is closely controlled.</P> <P>In an attempt to reduce the potential liability of addiction and abuse, New River Pharmaceuticals developed <strong>lisdexamfetamine dimesilate</strong>, an amphetamine prodrug consisting of d-amphetamine conjugated to L-lysine. The drug is therapeutically inactive until it is hydrolyzed in the digestive tract, and furthermore has a prolonged duration of effect, with efficacy lasting for a full treatment day. Data from phase II and III trials, conducted by New River in collaboration with development partner Shire, demonstrated statistically significant improvements in ADHD symptoms in patients aged 6-12 years receiving lisdexamfetamine at all doses tested (30, 50 and 70 mg) as compared to those given placebo. In human drug abuse studies, oral and intravenous administration of lisdexamfetamine produced subjective responses on a scale of &quot;drug-liking effects&quot; (DLE, a measure of relative preference among substance abusers, used in clinical abuse studies) that were less than those reported for d-amphetamine at equivalent doses.</P> <P>In February, the U.S. FDA approved lisdexamfetamine dimesilate (<em>Vyvanse</em>&reg;) for the treatment of attention deficit/hyperactivity disorder in pediatric patients. The label received with the approval letter includes information about the drug’s extended duration of effect and abuse-related drug-liking characteristics, which differentiate <em>Vyvanse</em>&reg; from other ADHD medications. The FDA has proposed that <em>Vyvanse</em>&reg; be classified as a Schedule II controlled substance, and this proposal has been accepted by the U.S. Drug Enforcement Administration (DEA). Pending final scheduling designation, product launch is anticipated in the second quarter of 2007. In related news, Shire announced just days prior to the NDA approval that it would acquire New River and, as a result, all rights to the product.</P> http://www.prous.com/molecules/default.asp?ID=156 <P>GlaxoSmithKline is developing <B>Daronrix&reg;</B>, a “mock-up” pandemic influenza vaccine for the prophylaxis of influenza infection. The vaccine candidate, an inactivated whole-virion H5N1 vaccine formulated with an alum salt adjuvant, is intended for use once a pandemic has officially been declared by the WHO/E.U. and would be modified to include the exact pandemic strain, once such a strain has been identified. The vaccine has been filed for approval in the E.U. In December 2006, a positive opinion was received in the E.U. for the treatment of influenza.</P> <P>Daronrix&reg; represents a first step in the preparation against a possible H5N1 pandemic. The benefit of this vaccine, according to the Committee for Medicinal Products for Human Use summary of positive opinion, “can mount an appropriate immune response in individuals that are immunologically naïve against the mock-up virus strain.” The submission dossier was based on a series of data, including a pivotal clinical trial involving 400 healthy adults that evaluated the safety, reactogenicity and immunogenicity of different doses of the candidate vaccine and compared it to different doses of nonadjuvanted H5N1 influenza vaccine. It was concluded from the study, that two doses containing at least 15 mg of H5N1 HA antigen are required to meet the European Medicines Agency (EMEA)'s licensing criteria for seroprotection rate (SP(3)70&#37;), seroconversion rate (SC(3)40&#37;) and seroconversion factor (2.5). The vaccine also had a safety and reactogenicity profile similar to non-adjuvanted vaccine. </P> <P>GSK has also submitted a second file to the European regulatory authorities for its second-generation H5N1 candidate vaccine. Upon licensure, this second vaccine could potentially be used as part of a proactive pre-pandemic vaccination campaign in advance of a pandemic and give broad protection against different H5N1 strains. This new-generation vaccine candidate could also be adapted for use as a pandemic vaccine once the flu strain causing the pandemic has been identified. Other companies known to be working on potential pandemic influenza vaccines (according to Integrity&reg;) include Novartis, whose MF59-adjuvanted H5N1 vaccine is also under review in the E.U.; as well as Baxter, CSL, Crucell, sanofi pasteur, Generex, Sinovac, PowderMed, MedImmune and the National Institute of Allergy and Infectious Diseases (NIH), each of which has a proprietary H5N1 pandemic influenza vaccine in early clinical testing.</P> http://www.prous.com/molecules/default.asp?ID=155 <P>Roche's R-744 (CERA, Mircera&reg;), the first continuous erythropoietin receptor activator, is in late-stage development for the treatment of renal anemia in chronic kidney disease (CKD) patients, including those on dialysis and not on dialysis. Unlike traditional erythropoietin-stimulating agents (ESAs), Mircera has a greatly reduced affinity for t