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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Curis phase 1 Cancer Trial for CUDC-427 Begins
CUDC-427, GDC-0917; RG-7459
Genentech Inc (Roche Holding AG)
Curis licenses GDC-0917 from Genentech
Curis Cancer Trial Begins
Curis Inc. has initiated patient dosing in a second Phase 1 dose-escalation study of CUDC-427 that is being conducted using a continuous, twice-daily oral dosing regimen in patients with advanced and refractory solid tumors or lymphoma.
FULL STORY
About CUDC-427 (GDC-0917)
CUDC-427 is an orally bioavailable small molecule that is designed to promote cancer cell death by antagonizing IAP proteins. IAP proteins are a family of functionally and structurally related proteins that promote cancer cell survival by inhibiting programmed cell death, also known as apoptosis, which is a normal process inherent in every cell. Using IAP proteins and other anti-apoptotic factors, cancer cells evade apoptosis in response to a variety of signals, including those provided by anti-cancer agents such as chemotherapy, or naturally occurring inflammatory and immune signals transmitted through members of the tumor necrosis factor, or TNF, family of factors. Evasion from apoptosis is a fundamental mechanism whereby human cancers develop resistance to standard anti-cancer treatments. IAP inhibitors such as CUDC-427 are designed to counteract the effects of IAP proteins, thus shifting the balance away from cancer cell survival and allowing apoptosis to proceed.
CUDC-427 was designed to mimic the endogenous IAP antagonist mitochondrial protein second mitochondria-derived activator of caspases/direct IAP-binding protein (Smac/DIABLO) that is released into the cytoplasm in response to pro-apoptotic stimuli. CUDC-427 has demonstrated single-agent and combination anti-tumor activity in mouse xenograft tumor models when administered orally on a daily schedule, and IND-enabling safety studies have shown it to be well tolerated when dosed daily by oral administration, potentially enabling sustained target inhibition.
In October 2010, an open-labeled, uncontrolled, dose-escalation, Phase I clinical trial of CUDC-427 (NCT01226277; IAM4914g) began in patients with refractory solid tumors or lymphoma. Genentech recently completed this Phase I clinical trial in which 42 people received daily oral doses of CUDC-427 for two weeks, followed by a one week rest period. This 21-day cycle is repeated until disease progression or study discontinuation for any other reason. The primary endpoints of the study include evaluating the safety and tolerability and the pharmacokinetics of CUDC-427 in people with solid tumors or lymphoma and determining the maximum-tolerated-dose and a potential recommended dose for further clinical studies. Secondary endpoints include a preliminary assessment of anti-tumor activity of CUDC-427 and evaluating pharmacodynamic markers. Genentech plans to present full study results at a medical conference in mid-2013. Please refer to http://www.clinicaltrials.gov for additional study details.
About Inhibitor of Apoptosis Proteins
Impairment of programmed cell death or apoptosis often contributes to the formation and progression of cancer, and evasion of apoptosis is one of the primary strategies by which cancer cells develop resistance to anticancer therapies. Inhibitor of apoptosis (IAP) proteins are a family of functionally and structurally related proteins which include X-linked IAP (XIAP), cellular IAPs (cIAP1 and cIAP2), and melanoma IAP (ML-IAP). They confer protection from death-inducing stimuli by exerting a range of biological activities that promote cancer cell survival and proliferation. Some even directly inhibit caspases, critical players in the execution of apoptosis.
Mutations, amplifications and chromosomal translocations of IAP genes are associated with various solid and hematologic cancer types, and increased IAP expression has been associated with an unfavorable prognosis and poor outcome for patients. As a consequence, IAP proteins are considered promising molecular targets for anticancer therapy.
Antibody Effective Against Norovirus
Antibody Effective Against Norovirus
Researchers have released data showing that a monoclonal antibody can neutralize human norovirus. Norovirus causes roughly 20 million cases of acute diarrhea and vomiting annually in the United States, alone. It is also responsible for roughly 800 deaths annually.
FULL STORY
What is Norovirus?
Norovirus is a stomach bug that sets in within 10 hours of transmission and usually lasts up to three days. It is completely different from the flu in that only your stomach is affected. While most people recover completely after three days, norovirus is more serious for young children, the elderly and people with other serious health conditions. Every year 70,000 people are hospitalized and 800 deaths are caused by the virus.
What are the symptoms?
The most common symptoms of norovirus include stomach pain, vomiting, diarrhea and nausea. Some people also experience a low-grade fever, headache and body ache. Because it is common to have continued vomiting and diarrhea during the three days of illness, dehydration is another concern for those affected.
How do you get it?
Norovirus is spread through direct contact with an infected person’s vomit or feces. Most commonly, unwashed hands can be attributed to spreading the virus through surfaces or food. The virus spreads quickly in enclosed spaces like cruise ships, nursing homes and schools.
What is the treatment?
Unfortunately, there are no medications to treat norovirus. Health care providers say the best thing to do is try to stay hydrated, rest and wait for the virus to run its course. People who are unable to keep fluids down may need to receive fluids intravenously.
How can you protect yourself?
Hand washing is the best defense against the norovirus, since no one is immune to the always-changing strains of the virus. However, new research has found hand sanitizers are not affective in killing the virus. Avoid direct contact with anyone who is infected and pay close attention to cleaning and preparing food. Also, anyone who is infected should not prepare food. Use disinfectants to wipe down all surfaces that have come in contact with someone who is infected. Also, launder infected clothes immediately on the longest wash cycle to help from spreading the virus.
CSIR, INDIA-WO PATENT–synthesis of amprenavir and saquinavir
amprenavir
saquinavir
A process for synthesis of syn azido epoxide and its use as intermediate in the synthesis of amprenavir and saquinavir
Published as ———WO-2013105118
Council of Scientific & Industrial Research
Inventors
Gadakh, Sunita, Khanderao; Rekula, Reddy, Santhosh; Sudalai, Arumugam
Publication date 18-JUL-2013
HIV protease inhibitor
Disclosed herein is a novel route of synthesis of syn azide epoxide of formu 5, which is used as a common intermdeiate for asymmetric synthesis of HIV protease inhibitors such as Amprenavir, Fosamprenavir, Saquinavir and formal synthesis of Darunavir and Palinavir obtained by Cobalt- catalyzed hydrolyti kinetic resolution of racemic anti-(2SR, 3SR) – 3 -azido – 4 -phenyl – 1, 2- epoxybutane (azido-epoxide
| IN2012DE82 | 10-JAN-2012 [priority] |
Biosimilars applications under review by EMA – 2013 Q2
The European Medicines Agency (EMA) is the body responsible for approval of biosimilars within the EU. A legal framework for approving biosimilars was established in 2003. Approval of biosimilars is based on an abbreviated registration process, which allows biosimilars manufacturers to provide a reduced package of information compared to originator drugs, provided they can prove ‘similarity’ to the originator or ‘reference drug’.
read all at
http://www.gabionline.net/Biosimilars/General/Biosimilars-applications-under-review-by-EMA-2013-Q2
First biosimilar filgrastims launched in Japan
International nonproprietary name: Filgrastim
Chemical name: N-L- Methionyl colony-stimulating factor (human genetically engineered); non-glycated protein consisted of 175 amino acids.
Chemical name: N-L- Methionyl colony-stimulating factor (human genetically engineered); non-glycated protein consisted of 175 amino acids.
Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes.[1] It is produced by recombinant DNA technology. The gene for human granulocyte colony-stimulating factor is inserted into the genetic material of Escherichia coli. The G-CSF then produced by E. coli is different from G-CSF naturally made in humans.
Hematopoietic growth factor. Interacting with receptors on the surface of hematopoietic cells it regulates production and release of neutrophils from the bone marrow to the peripheral blood. Dose dependant number growth of neutrophils with normal or increased functional activity is passing for 24 hours.
Filgrastim is marketed under several brand names, including Neupogen (Amgen), Imumax(Abbott Laboratories), Grafeel (Dr. Reddy’s Laboratories), Neukine (Intas Biopharmaceuticals), Emgrast (Emcure Pharmaceuticals), Religrast (Reliance Life Sciences), Zarzio (Sandoz), Nufil (Biocon) and others.
Apricus Biosciences is currently developing and testing a product under the brand nameNupen which can deliver filgrastim through the skin to improve post-chemotherapy recovery of neutrophil counts.
Filgrastim is also used to increase the number of hematopoietic stem cells in the blood before collection by leukapheresis for use in hematopoietic stem cell transplantation.Filgrastim is used to treat neutropenia,[2] stimulating the bone marrow to increase production of neutrophils. Causes of neutropenia include chemotherapy and bone marrow transplantation.
Filgrastim should not be used in patients with known hypersensitivity to E. coli-derived proteins.
The most commonly observed adverse effect is mild-to-moderate bone pain after repeated administration and local skin reactions at the site of injection.[3] Other observed adverse effects include serious allergic reactions (including a rash over the whole body, shortness of breath, wheezing, dizziness, swelling around the mouth or eyes, fast pulse, and sweating), ruptured spleen (sometimes resulting in death), alveolar hemorrhage, acute respiratory distress syndrome, and hemoptysis.[3] Severe sickle cell crises, in some cases resulting in death, have been associated with the use of filgrastim in patients with sickle cell disorders.[4]
Drug interactions between filgrastim and other drugs have not been fully evaluated. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution.
Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes; this should be considered when interpreting bone-imaging results.[5]
Filgrastim has not been studied in pregnant women and its effects on unborn babies is unknown. If taking filgrastim while pregnant, it is possible that traces of the drug could be found in the baby’s blood. It is not known if the drug can get into human breast milk.
- Beveridge, R. A.; Miller, J. A.; Kales, A. N.; Binder, R. A.; Robert, N. J.; Harvey, J. H.; Windsor, K.; Gore, I. et al. (1998). “A Comparison of Efficacy of Sargramostim (Yeast-Derived RhuGM-CSF) and Filgrastim (Bacteria-Derived RhuG-CSF) in the Therapeutic Setting of Chemotherapy-Induced Myelosuppression”. Cancer Investigation 16 (6): 366–373. doi:10.3109/07357909809115775.PMID 9679526. edit
- Crawford, J.; Glaspy, J. A.; Stoller, R. G.; Tomita, D. K.; Vincent, M. E.; McGuire, B. W.; Ozer, H. (2005). “Final Results of a Placebo-Controlled Study of Filgrastim in Small-Cell Lung Cancer: Exploration of Risk Factors for Febrile Neutropenia”. Supportive Cancer Therapy 3 (1): 36–46. doi:10.3816/SCT.2005.n.023. PMID 18632435. edit
- Neupogen “Neupogen: Patient Information Leaflet”. Amgen. Retrieved 24 June 2013.
- “NEUPOGEN® Patient Guide”. Amgen. Retrieved 24 June 2013.
- “Neupogen”. RxList. 4 June 2012. Retrieved 23 June 2013.
- Budiono Santoso; Chris J. van Boxtel; Boxtel, Christoffel Jos van (2001). Drug benefits and risks: international textbook of clinical pharmacology. New York: Wiley. ISBN 0-471-89927-5.
- “Neupogen information”. Retrieved 20 October 2005.
Genentech announced positive results from the Phase 3 CLL11 study, Leukemia Trial
Afutuzumab
Obinutuzumab (GA101)
Genentech announced positive results from the Phase 3 CLL11 study. At a pre-planned interim analysis, an independent data monitoring committee determined that the study met its primary endpoint showing that GA101 plus chlorambucil helped people live significantly longer without their disease worsening (progression-free survival; PFS) compared to Rituxan (rituximab) plus chlorambucil.
The CLL11 study is being conducted in cooperation with the German CLL Study Group (GCLLSG). These final data were reached well ahead of the target completion date in 2014 as a result of the magnitude of difference seen between the two study arms.
Afutuzumab is a monoclonal antibody being developed by Hoffmann-La Roche Inc. for the treatment of lymphoma.[1] It acts as an immunomodulator.[2][3] It was renamed obinutuzumab in 2009.[4]
Class/mechanism: Glyco-engineered anti-CD20 IgG1 type II monoclonal antibody. Engineered with a modified elbow hinge residue (valine instead of leucine at Kabat position 11) and a glyco-engineered Fc region, which is postulated to enhance its immunomodulatory effect.[1]
Route: IV
Extravasation: no information
For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer.
- Robak, T (2009). “GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies”. Current opinion in investigational drugs (London, England : 2000) 10 (6): 588–96. PMID 19513948.
- Statement On A Nonproprietary Name Adopted By The Usan Council – Afutuzumab, American Medical Association.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
- International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization.
| FULL STORYread all |
Alkermes unveils three new drug candidates
Alkermes has unveiled three new drug candidates, including: a monomethyl fumarate (MMF) prodrug programme for the treatment of multiple sclerosis; ALKS 7106 for the treatment of pain; and RDB 1419, a cancer immunotherapy candidate based on interleukin-2 (IL-2) and its receptors, Alkermes’ first proprietary biologic.
According to Alkermes, these drug candidates demonstrate the company’s focus on unmet medical needs in specific patient populations and show the productivity of its expanded R&D capabilities.
read all at
http://www.manufacturingchemist.com/news/article_
page/Alkermes_unveils_three_new_drug_candidates/90167
FDA Approves New Drug to Treat Nephropathic Cystinosis
CHICAGO—The U.S. Food and Drug Administration (FDA) has recently approved PROCYSBI(cysteamine bitartrate), a delayed release capsule for treating nephropathic cystinosis in adults and children 6 years and older.
Ann and Robert H. Lurie Children’s Hospital of Chicago served as one of three United States sites for the landmark study and patients came from all over North America to be seen by lead investigator, Craig B Langman, M.D., The Isaac A Abt, M.D. professor of Kidney Diseases at Northwestern University Feinberg School of Medicine and head of Kidney Diseases at Lurie Children’s
Astellas pharma announced today that the U.S. Food and Drug Administration (FDA) has approved Astagraf XL (tacrolimus extended-release capsules) for the prophylaxis of organ rejection in patients receiving a kidney transplant with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction
Tacrolimus
July 19, 2013 /PRNewswire/ — Astellas Pharma US, Inc. (“Astellas”), a U.S. subsidiary of Tokyo-based Astellas Pharma Inc., announced today that the U.S. Food and Drug Administration (FDA) has approved Astagraf XL (tacrolimus extended-release capsules) for the prophylaxis of organ rejection in patients receiving a kidney transplant with mycophenolate mofetil (MMF) and corticosteroids, with or without basiliximab induction.
“Each transplant recipient is different and requires a personalized treatment approach. The approval of Astagraf XL marks an important milestone in post-transplant care as it provides physicians with a new treatment option for kidney t recipients,” said Sef Kurstjens, M.D., PhD., chief medical officer, Astellas Pharma, Inc. “Astellas is pleased to continue our more than 20-year commitment to the field of transplant immunology.”
Tacrolimus (also FK-506 or fujimycin, trade names Prograf, Advagraf, Protopic) is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient’s immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, and the skin condition vitiligo.
It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It reduces interleukin-2 (IL-2) production by T-cells.
Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.It is produced by a type of soil bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from ‘Tsukuba macrolide immunosuppressant’.
Tacrolimus 0.1%
Tacrolimus was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.
The branded version of the drug is owned by Astellas Pharma, and is sold under the trade names Prograf given twice daily, Advagraf, a sustained release formulation allowing once daily dosing, and Protopic (Eczemus in Pakistan by Brookes Pharma), the topical formulation. Advagraf is available in 0.5, 1, 3 and 5 mg capsules, the ointment is concentrations of 0.1% and 0.03%.
A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus.Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus. A second Phase 3 trial in de novo patients is ongoing.
Benzoxaboroles: A New Potential Drug for African Sleeping Sickness
Life cycle of the Trypanosoma brucei parasites, source: CDC
Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity, and the complexity of treatment regimens.
We have discovered and optimized a series of benzoxaborole- 6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.
Human African trypanosomiasis (HAT), more commonly known as African sleeping sickness, is caused by two subspecies of the kinetoplastid parasite Trypanosoma brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, which are introduced into the victim through the bite of the tse-tse fly. Endemic across sub-Saharan Africa, tens of thousands of people are infected each year, with millions at risk of contracting the disease. If not treated early in the progression of the disease, the T. brucei parasites migrate across the blood–brain barrier and reside in brain tissue, ultimately causing neuronal death leading to a multitude of neurological symptoms including hallucinations, sleep disorders, coma and, ultimately, death.
Current treatment options for HAT are inadequate due to lack of efficacy, particularly once the parasites have migrated to the brain (stage 2 HAT), toxicity and the complexity of treatment regimens. The most commonly used treatment for stage 2 HAT, melarsoprol is highly toxic, with an estimated 5–10% drug-related mortality. A more recent drug, eflornithine, while effective against T.b. gambiense, is not effective against T.b. rhodesiense, and must be administered in a complex intravenous regime that is impractical in disease-endemic areas.
Consequently, there is an urgent need for new drugs to treat HAT and, in particular, a need for a safe, orally active drug that is effective against all known strains of T. brucei and is effective in stage 2 HAT
http://www.drugdiscoveryonline.com/doc/benzoxaboroles-african-trypanosomiasis-drug-0001
New Drug Approvals 