Home » 2013 (Page 16)

Yearly Archives: 2013

A class of drugs used to treat parasitic infections such as malaria may also be useful in treating cancers and immune-related diseases, a new WSU-led study has found.

Researchers discovered that simple modifications to the drug furamidine have a major impact on its ability to affect specific human proteins involved in the on-off switches of certain genes.

“This was rather unexpected, given how relatively simple the molecules are that we modified and how difficult it has been to affect these proteins,” said Gregory Poon, pharmaceutical scientist at Washington State University.

The proteins– known as transcription factors– regulate the expression of genes in a highly coordinated and intricate manner, making them attractive targets for therapeutic drugs. But it has proven difficult to design drugs to affect them, Poon said.

“For this reason, they have been called undruggable,” he said. “Recently, however, scientists have been making headway in…

View original post 260 more words

Pramlintide

November 15, 2013 3:31 am / 3 Comments on Pramlintide

Pramlintide (Symlin), a synthetic version of amylin, is a 37-amino acid peptide that is co-secreted with insulin by pancreatic β-cells. It was developed and approved in 2005 by the FDA for use in US patients with type I and II diabetes in conjunction with the administration of prandial insulin to improve postprandial glycemic control

Pramlintide

Pramlintide (Symlin) is a relatively new adjunct for diabetes (both type 1 and 2), developed by Amylin Pharmaceuticals (now a wholly owned subsidiary of Bristol Myers-Squibb). Pramlintide is delivered as an acetate salt.

Pramlintide is an analogue of amylin, a small peptide hormone that is released into the bloodstream by the β-cells of the pancreas along with insulin, after a meal.^[1] Like insulin, amylin is completely absent in individuals with Type I diabetes.^[2]

Reduction in glycated hemoglobin and weight loss have been shown in insulin-treated patients with type 2 diabetes taking pramlintide as an adjunctive therapy.^[3]

By augmenting endogenous amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying, promoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon, a catabolic hormone that opposes the effects of insulin and amylin. Pramlintide also has effects in raising the acute first-phase insulin response threshold following a meal.

Pramlintide has been approved by the FDA, for use by Type 1 and Type 2 Diabetics who use insulin.^[4]Pramlintide allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating. Apart from insulin analogs, pramlintide is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin in the early 1920s.

Design and structure

Since native human amylin is highly amyloidogenic and potentially toxic, the strategy for designing pramlintide was to substitute residues from rat amylin, which is not amyloidogenic (but would presumably retain clinical activity). Proline residues are known to be structure-breaking residues, so these were directly grafted into the human sequence.

Amino acid sequences:

Pramlintide: KCNTATCATQRLANFLVHSSNNFGPILPPTNVGSNTY-(NH₂) Amylin: KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY-(NH₂) Rat amylin: KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY-(NH₂)

Pramlintide as protein is (positively charged).

Jones MC (2007). “Therapies for diabetes: pramlintide and exenatide” (pdf). American Family Physician 75 (12): 1831–5. PMID 17619527.
Edelman, Steve; Maier, Holly; Wilhelm, Ken (2008). “Pramlintide in the Treatment of Diabetes Mellitus”.BioDrugs 22 (6): 375–386. doi:10.2165/0063030-200822060-00004. ISSN 1173-8804.
Hollander, Priscilla; Maggs, David G.; Ruggles, James A.; Fineman, Mark; Shen, Larry; Kolterman, Orville G.; Weyer, Christian (2004). “Effect of Pramlintide on Weight in Overweight and Obese Insulin-Treated Type 2 Diabetes Patients” (pdf). Obesity 12 (4): 661–668. doi:10.1038/oby.2004.76.ISSN 1930-7381.
Ryan GJ, Jobe LJ, Martin R (2005). “Pramlintide in the treatment of type 1 and type 2 diabetes mellitus”. Clinical therapeutics 27 (10): 1500–12. doi:10.1016/j.clinthera.2005.10.009. PMID 16330288.

www.symlin.com – product website
www.amylin.com – Symlin page on the Amylin Pharmaceuticals website

Pramlintide Acetate
Pramlintide acetate is a relatively new adjunct treatment for diabetes (both type 1 and 2).

Pramlintide Acetate, 196078-30-5,

Synonym	Pramlintide Acetate,Pramlintide acetate hydrate
Molecular Formula	C171H267N51O53S2.X(C2H4O2).X(H2O)
Molecular Weight	3949.39

FDA Approves Implanted Brain Stimulator for Epilepsy

November 15, 2013 3:27 am / 2 Comments on FDA Approves Implanted Brain Stimulator for Epilepsy

epilepsy

THURSDAY Nov. 14, 2013 — The U.S. Food and Drug Administration on Thursday gave its approval to a new implanted device that lowers the rate of seizures among people with epilepsy

http://www.drugs.com/news/fda-approves-implanted-brain-stimulator-epilepsy-48978.html

EPROSARTAN MESYLATE

November 15, 2013 3:18 am / 3 Comments on EPROSARTAN MESYLATE

TEVETEN® (eprosartan mesylate) is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, TEVETEN® is chemically described as the monomethanesulfonate of (E)-2-butyl-1 -(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5 -acrylic acid.

Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is:

EPROSARTAN MESYLATE

tevetenEprosartan mesilate, SK&F-108566-J(?, SK&F-108566, Teveten SB, Navixen, Regulaten, Tevetenz, Teveten

US 5656650

exp Aug 12, 2014

CAS EPROSARTAN

144143-96-4

133040-01-4


Chemical Name:	Eprosartan mesylate
Synonyms:	EPROSARTAN MESYLATE;Eprosartan Methanesulfonate;4-[[2-butyl-5-(2-carboxy-3-thiophen-2-yl-prop-1-enyl)-imidazol-1-yl]methyl]benzoic acid mesylate;4-({2-butyl-5-[(1E)-2-carboxy-2-(thiophen-2-ylMethyl)eth-1-en-1-yl]-1H-iMidazol-1-yl}Methyl)benzoic acid;(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid Methanesulfonate;(αE)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid MonoMethanesulfonate
CBNumber:	CB4842192
Molecular Formula:	C24H28N2O7S2
Formula Weight:	520.61832

Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten byAbbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in India and by Abbott Laboratorieselsewhere. It is sometimes paired with hydrochlorothiazide, marketed in the US as Teveten HCT and elsewhere as TevetenPlus.

The drug acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding ofangiotensin II to AT₁ receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympathetic norepinephrine production, further reducing blood pressure.

As with other angiotensin II receptor antagonists, eprosartan is generally better tolerated than enalapril (an ACE inhibitor), especially among the elderly.^[1]

^{Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding of angiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympathetic norepinephrine production, further reducing blood pressure.}

Ruilope L, Jäger B, Prichard B (2001). “Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial”. Blood Press. 10 (4): 223–9. doi:10.1080/08037050152669747. PMID 11800061.

Teveten website

PAT APR EXP

Canada	2250395	2005-09-06	2017-03-26
Canada	2115170	2004-05-25	2012-08-12
United States	5656650	1994-08-12	2014-08-12
United States	5185351	1993-02-09	2010-02-09


Canada	2115170	2004-05-25	2012-08-12
United States	5656650	1994-08-12	2014-08-12
Canada	2250395	2005-09-06	2017-03-26

J Med Chem1991,34,(4):1514-7

J Med Chem1993,36,(13):1880-92

Synth Commun1993,23,(22):3231-48

AU 9056901, EP 403159, JP 91115278, US 5185351.

Drugs Fut1997,22,(10):1079

Eprosartan mesylate was developed successfully by SmithKline Beecham Corporation in 1997, and marketed in Germany in 1998 under the trade-name Teveten and in the United States later in 1999. Eprosartan mesylate, as an angiotensin II receptor blocker, is an antihypertensive drug of the latest generation. Eprosartan mesylate is potent to lower systolic and diastolic pressures in mild, moderate and severe hypertensive patients, and is safe and tolerable. Eprosartan mesylate is rapidly absorbed when administrated orally, with a bioavailability of 13% and a protein binding rate of 98%. The blood peak concentration and AUC (Area Under Curve) can be elevated by about 50% in patients with liver and kidney dysfunction, or fullness after administration, and can be elevated by 2 to 3 folds in elderly patients. Eprosartan mesylate has a structure shown as follows:

U.S. Pat. No. 5,185,351 discloses a method for preparing eprosartan mesylate using Eprosartan and methanesulfonic acid in isopropanol (U.S. Pat. No. 5,185,351, Example 41 (ii)). However, it is found when following this method for preparing eprosartan mesylate in industry, an esterification reaction can occur between eprosartan and isopropanol and the following two impurities can be generated:

In addition to the above two esterification impurities, the salifying method provided by the above patent is prone to produce isopropyl mesylate. Considering currently known potential risk of gene toxicity of methylsulfonic acid ester on human as well as the stringent requirements of methylsulfonic acid ester from the Europe and the America authorities, it is important to produce eprosartan mesylate in a non-alcohol solvent during the process of producing eprosartan mesylate, since it avoids the formation of methylsulfonic acid ester and the residue thereof in the final product. Since the dosage of eprosartan mesylate is high, it is particularly important to strictly control methylsulfonic acid ester in eprosartan mesylate.

In addition, for the above salifying method, solid eprosartan is suspended in propanol at a low temperature, then methanesulfonic acid is added, about ten seconds later a great deal of eprosartan mesylate precipitate is obtained. Therefore, solid eprosartan may be embedded by the precipitated eprosartan mesylate. Since isopropyl alcohol has a high viscosity at low temperature, a heavy filtering operation burden is needed to obtain solid from isopropanol, and the obtained solid contains quite an amount of isopropanol.

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

…………………………………………………………………………………………………….

WO 1998035962 A1

…………………………………………………………………………………………..

Big boost for Incyte as Jakafi shines in PhII

November 14, 2013 11:47 am / 2 Comments on Big boost for Incyte as Jakafi shines in PhII

New Drug Approvals

ruxolitinib

Top-line results from a Phase II trial showed that its JAK inhibitor Jakafi (ruxolitinib), in combination with Roche’s Xeloda (capecitabine), improved survival in some patients with recurrent or treatment refractory advanced pancreatic cancer

http://www.pharmatimes.com/Article/13-08-

22/Big_boost_for_Incyte_as_Jakafi_shines_in_PhII.aspx

Ruxolitinib (trade names Jakafi and Jakavi, by Incyte Pharmaceuticals and Novartis) is a drug for the treatment of intermediate or high-risk myelofibrosis, a type of bone marrow cancer.It is also being investigated for the treatment of other types of cancer (such as lymphomas and pancreatic cancer), for polycythemia vera, and for plaque psoriasis.
The phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor-I (COMFORT-I) and COMFORT-II trials showed significant benefits by reducing spleen size, relieving debilitating symptoms, and improving overall survival.

Mechanism of action

Ruxolitinib is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.
Side effects

Immunologic side effects have included herpes zoster (1.9%) and case reports of…

View original post 638 more words

QbD: new Guidance from EMA and FDA

November 14, 2013 10:49 am / 3 Comments on QbD: new Guidance from EMA and FDA

DRUG REGULATORY AFFAIRS INTERNATIONAL

QbD: new Guidance from EMA and FDA

The European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) have published a joint question-and-answer document that provides further guidance on the quality-by-design concept. Read more.

http://www.gmp-compliance.org/ecanl_654_0_news_4015_8280,8356,Z-PDM_n.html

The Quality by Design (QbD) concept has been introduced by the International Conference on Harmonisation (ICH) document Q8, supported by Q9, Q10 and also Q11. In the meantime it is well-known within the pharmaceutical industry. However many companies still struggle with the implementation. Both the European Medicine Agency (EMA) and the U.S. Food and Drug Agency (FDA) are supporting the pharmaceutical industry in the employment of the paradigm. Now, EMA and FDA have published a second joint question-and-answer document that provides further guidance on the quality-by-design concept.

The new document focuses on ‘design space verification’ and reflects conclusions reached in the on-going parallel assessment, which was launched in 2011. The objective of the parallel…

View original post 388 more words

Chugai Pharma to commercialize Helsinn’s Anamorelin for anorexia-cachexia syndrome in Germany, France, Benelux, UK and Ireland

November 14, 2013 7:10 am / 3 Comments on Chugai Pharma to commercialize Helsinn’s Anamorelin for anorexia-cachexia syndrome in Germany, France, Benelux, UK and Ireland

LUGANO, Switzerland, November 12, 2013 /PRNewswire/ —

Swiss Pharma Group Helsinn seals an alliance with Japanese company Chugai by granting exclusive distribution & licensing rights to commercialize its innovative phase III ghrelin receptor agonist in Germany, France, Benelux, UK andIreland

Swiss-based Helsinn group has granted Chugai Pharma Marketing Ltd., a wholly-owned subsidiary of Chugai Pharmaceutical Co., Ltd., exclusive commercialization rights to their innovative ghrelin receptor agonist, anamorelin, for the three major European pharma markets.

Anamorelin is a new first-in-class, oral, once daily drug, currently in phase III for the treatment of anorexia-cachexia in NSCLC, a detrimental multifactorial disorder that affects over 50% of people with cancer and in which systemic inflammation, reduced food intake and altered metabolism contribute to loss of muscle mass and reduction of body weight leading to reduced quality of life, functional impairment and decreased survival.

http://www.prnewswire.com/news-releases/helsinn-and-chugai-pharma-marketing-enter-into-agreement-for-rights-of-anamorelin-currently-in-development-for-treatment-of-anorexia-cachexia-syndrome-related-to-non-small-cell-lung-cancer-in-top-eu-markets-231514911.html

Anamorelin is a synthetic orally active ghrelin receptor agonist which is under development for the management of non-small lung cancer associated cachexia/anorexia.
Development status: Phase 3
Appetite loss; Aging; Bone injury; Cachexia

Anamorelin HCl

M. Wt	583.16
Formula	C31H43ClN6O3

CAS No.	861998-00-7
Synonyms	RC 1291; RC1291; RC 1291-HCl; ONO-7643; ONO7643; ONO 7643.
Chemical Name	2-amino-N-((R)-1-((R)-3-benzyl-3-(1,2,2-trimethylhydrazinecarbonyl)piperidin-1-yl)-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-2-methylpropanamide hydrochloride

Mast Ischemia Drug Gets Orphan Drug Designation

November 14, 2013 3:46 am / 1 Comment on Mast Ischemia Drug Gets Orphan Drug Designation

Wed, 11/13/2013

Mast Therapeutics Inc. announced that the U.S. Food and Drug Administration (FDA) has designated MST-188 for the treatment of acute limb ischemia as an orphan drug.http://www.dddmag.com/news/2013/11/mast-ischemia-drug-gets-orphan-drug-designation

MST-188 (purified poloxamer 188)

MST-188 is a purified form of a nonionic, triblock copolymer (poloxamer 188). It is an investigational agent that binds to hydrophobic surfaces on damaged cells and improves membrane hydration and lowers adhesion and viscosity, particularly under low shear conditions. MST-188 has the potential to reduce ischemic tissue injury and end-organ damage by restoring microvascular function, which is compromised in a wide range of serious and life-threatening diseases and conditions. We initially are developing MST-188 as a treatment for complications arising from sickle cell disease.

How MST-188 Works…

Background

Non-purified forms of poloxamer 188 (P188) have been used in foods, drugs and cosmetics since the 1950s. In the 1980s, extensive research on the mechanisms and potential clinical applications of P188 was conducted. Research has demonstrated that P188 binds to hydrophobic surfaces that develop when cells are damaged and restores normal hydrated surfaces, while having little or no activity in normal, healthy tissues. Research also has demonstrated that P188 prevents adhesion and aggregation of soluble fibrin and formed elements in the blood and maintains the deformability of red blood cells, the non-adhesiveness of unactivated platelets and granulocytes and the normal viscosity of blood. In addition, it is believed that P188 is not metabolized, but is excreted unchanged in the urine with a half-life of approximately four to six hours.

Formulations of P188 (non-purified and purified) have been studied in clinical trials involving nearly 4,000 individuals. It has been evaluated in the clinic to treat acute myocardial infarction, sickle cell disease and malaria, including a 2,950-patient, randomized, controlled study of P188 (non-purified) in acute myocardial infarction. The effectiveness of P188 also has been investigated in nonclinical studies of stroke, hemorrhagic shock, bypass surgery, adult respiratory distress syndrome, neurologic protection in deep hypothermic circulatory arrest, vasospasm, spinal cord injury, angioplasty, frostbite, amniotic fluid embolism, acute ischemic bowel disease and burns.

MST-188

Our(mast) purified form of P188, or purified P188, which is the active ingredient in MST-188, was designed to eliminate certain low molecular weight substances present in P188 (non-purified), which we believe were primarily responsible for the moderate to moderately severe elevations in serum creatinine levels (acute renal dysfunction) observed in prior clinical studies of P188 (non-purified). Purified P188 has been evaluated in multiple clinical studies by a prior sponsor, including a 255-patient, phase 3 study. In that study, purified P188 was generally well tolerated and there were no clinically significant elevations in serum creatinine among subjects who received purified P188 compared to placebo.

We believe that, as a rheologic, antithrombotic and cytoprotective agent, MST-188 has potential application in treating a wide range of diseases and conditions resulting from microvascular-flow abnormalities.

Sickle Cell Disease Market & Opportunity

More than $1.0 billion is spent annually in the U.S. to treat patients with sickle cell disease. Sickle cell disease is a genetic disorder characterized by the “sickling” of red blood cells, which normally are disc-shaped, deformable and move easily through the microvasculature carrying oxygen from the lungs to the rest of the body. Sickled, or crescent-shaped, red blood cells, on the other hand, are rigid and sticky and tend to adhere to each other and the vascular endothelium. Patients with sickle cell disease are known to experience severely painful episodes associated with the obstruction of small blood vessels by sickle-shaped red blood cells. These painful episodes are commonly known as acute crisis or vaso-occlusive crisis. Reduced blood flow to organs and bone marrow during vaso-occlusive crisis not only causes intense pain, but can result in tissue death, or necrosis. The frequency, severity and duration of these acute crises can vary considerably.

We (mast) estimate that, in the U.S., sickle cell disease results in over 95,000 hospitalizations and, in addition, approximately 69,000 emergency department treat-and-release encounters each year. When a patient with sickle cell disease makes an institutional visit, vaso-occlusive crisis is the primary diagnosis in approximately 77% of hospital admissions and 64% of emergency room treat-and-release encounters. In addition, although the number is difficult to measure, we estimate that the number of untreated sickle cell crisis events is substantial and in the hundreds of thousands in the U.S. each year. We believe that, if MST-188 is approved, as people with sickle cell disease are made aware of the new therapy, more people who suffer from acute crisis will seek treatment.

Development Status

We (mast) have initiated a Phase 3 clinical study of MST-188 for the treatment of sickle cell disease. The primary objective will be to demonstrate that MST-188 reduces the duration of vaso-occlusive crisis in patients with sickle cell disease. Please see our Clinical Trials page for more information regarding our phase 3 study of MST-188. In addition to the phase 3 study, we plan to conduct a number of smaller-scale clinical studies to further assess the efficacy, safety and tolerability of MST-188, and expect these studies to overlap with the phase 3 study.

U.S. Food and Drug Administration Approves IMBRUVICA™ (ibrutinib) as a Single Agent for Patients with Mantle Cell Lymphoma

November 14, 2013 1:17 am / 2 Comments on U.S. Food and Drug Administration Approves IMBRUVICA™ (ibrutinib) as a Single Agent for Patients with Mantle Cell Lymphoma

FDA OKs ‘Breakthrough’ Drug Imbruvica

U.S. Food and Drug Administration Approves IMBRUVICA™ (ibrutinib) as a Single Agent for Patients with Mantle Cell LymphomaWho Have Received at Least One Prior Therapy, a rare and aggressive type of blood cancer
Corporate Conference Call Scheduled Today at 10:00 AM PT, November 13, 2013http://www.pharmalive.com/fda-oks-breakthrough-drug-imbruvica

SUNNYVALE, Calif., Nov. 13, 2013 /PRNewswire/ — Pharmacyclics, Inc. (NASDAQ: PCYC) today announced that the U.S. Food and Drug Administration (FDA) has approved IMBRUVICA™ (ibrutinib) as a single agent for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.1 This indication is based on overall response rate (ORR). An improvement in survival or disease-related symptoms has not been established. IMBRUVICA is a new agent that inhibits the function of Bruton’s tyrosine kinase (BTK).1 BTK is a key signaling molecule of the B-cell receptor signaling complex that plays an important role in the survival of malignant B cells.2,3,4 IMBRUVICA blocks signals that stimulate malignant B cells to grow and divide uncontrollably.1,5http://www.pharmalive.com/fda-oks-breakthrough-drug-imbruvica

Ibrutinib (USAN,^[1] also known as PCI-32765 and marketed in the U.S. under the name Imbruvica) is a drug approved by the US FDA on November 13, 2013 for the treatment of mantle cell lymphoma.^[2] It is an orally-administered, selective and covalent inhibitor of the enzyme Bruton’s tyrosine kinase (BTK).^[3]^[4]^[5] Ibrutinib is currently under development by Pharmacyclics, Inc andJohnson & Johnson‘s Janssen Pharmaceutical division for B-cell malignancies including chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and multiple myeloma.^[6]^[7]^[8] Ibrutinib was first designed and synthesized at Celera Genomics which reported in 2007 a structure-based approach for creating a series of small molecules that inactivate BTK through covalent binding to cysteine-481 near the ATP binding domain of BTK.^[3] These small molecules irreversibly inhibited BTK by using a Michael acceptor for binding to the target cysteine. In April 2006, Pharmacyclics acquired Celera’s small molecule BTK inhibitor discovery program, which included a compound, PCI-32765 that was subsequently chosen for further preclinical development based on the discovery of anti-lymphoma properties in vivo.^[9] Since 2006, Pharmacyclics’ scientists have advanced the molecule into clinical trials and identified specific clinical indications for the drug. It also has potential effects against autoimmune arthritis.^[10]

Statement on a Nonproprietary Name Adopted by the USAN Council
FDA Press Release
Pan, Z; Scheerens, H; Li, SJ; Schultz, BE; Sprengeler, PA; Burrill, LC; Mendonca, RV; Sweeney, MD; Scott, KC; Grothaus, Paul G.; Jeffery, Douglas A.; Spoerke, Jill M.; Honigberg, Lee A.; Young, Peter R.; Dalrymple, Stacie A.; Palmer, James T. (2007). “Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase”. ChemMedChem 2 (1): 58–61.doi:10.1002/cmdc.200600221. PMID 17154430.
Celera Genomics Announces Sale of Therapeutic Programs to Pharmacyclics
United States patent 7514444
Janssen Biotech, Inc. Announces Collaborative Development and Worldwide License Agreement for Investigational Anti-Cancer Drug, PCI-32765
Clinical trials involve PCI-32765
Clinical trials involve ibrutinib
Honigberg, LA; Smith, AM; Sirisawad, M; Verner, E; Loury, D; Chang, B; Li, S; Pan, Z; Thamm, DH; Miller, RA; Buggy, JJ (2010). “The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy”. Proceedings of the National Academy of Sciences of the United States of America 107 (29): 13075–80. doi:10.1073/pnas.1004594107. PMC 2919935.PMID 20615965.
Chang, BY; Huang, MM; Francesco, M; Chen, J; Sokolove, J; Magadala, P; Robinson, WH; Buggy, JJ (2011). “The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells”. Arthritis Research & Therapy 13 (4): R115. doi:10.1186/ar3400.PMC 3239353. PMID 21752263.

Necitumumab

November 13, 2013 11:54 am / 1 Comment on Necitumumab

Necitumumab

Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR), which is a target in several anti-cancer treatments because it sparks cancer progression, both by promoting angiogenesis, or the formation of new blood vessels for tumors, and by inhibiting apoptosis, or cell death. Recently approved therapies for non-squamous NSCLC, including afatinib and erlotinib, target specific EGFR mutations, but those drugs are used to treat patients with nonsquamous histology.Lilly did not provide specific data regarding the results of the trial, but the company announced that it plans to present that data at a scientific meeting next year, and to request a review of the drug by regulatory authorities before the end of 2014.

Necitumumabis one of three monoclonal antibodies in Phase III
development that targets EGFR, the target of the approved antibodies
cetuximab and panitumumab. However, necitumumab is a fully human
IgG1 antibody, distinguishing it from both the approved agents.
Necitumumab is directed against the ligand binding site of EGFR and is
being co-developed by Eli Lilly and Bristol-Myers Squibb in the United
States, Canada, and Japan, while Eli Lilly alone is developing it for other
markets. Necitumumabfirst entered clinical development in 2004 and
is now in Phase III development for the treatment of non–small-cell
lung cancer and Phase II for the treatment of colorectal cancer. The
primary indication chosen further distinguishes necitumumabfrom both
cetuximab and panitumumab, but it is an indication for which EGFR
kinase inhibitors such as erlotinib are approved.
In December 2009, Eli Lilly stressed the long half-life of necitumumab
(7–10 days, which permits dosing at 2–3 week intervals) and its potential
both for reduced hypersensitivity reactions (i.e., better tolerability) and
for induced host-mediated anticancer activity. In addition, it highlighted
that necitumumabdisplays similar or superior activity to cetuximab
in anticancer models. Preliminary data were presented from the Phase
II study in colorectal cancer showing antitumor activity in 73% of 44
patients treated with necitumumabplus FOLFOX.
Both Phase III studies in non–small-cell lung cancer are in stage IV
disease and in groups of 947 patients treated with necitumumabplus
cisplatin and a second agent. The INSPIRE study in non-squamous
disease began in November 2009 and uses pemetrexed as the second
drug, while the SQUIRE study commenced in January 2010 in
squamous disease and uses gemcitabine. Both studies have primary
completion dates in late 2011 and study completion dates of mid-2012,
which points to BLA submission in 2013.

A Phase I study in patients with solid tumors suggested that skin
toxicity was the dose-limiting toxicity and suggested that 800 mg of
necitumumab (at weekly or fortnightly intervals) be the maximum dose
(Kuenen et al. 2010).16 This dose was employed in the initial colorectal
cancer study, at 14-day intervals, which revealed a 60% partial response
(Taberno et al. 2008).17
The development strategy for necitumumab appears to have been
designed to establish it initially in a major indication where it will not
be competing with established antibody products, while seeking
to exploit the reported advantages over cetuximab appears to be
a secondary priority. While the reported Phase II data are very
encouraging, it will be some time before a better assessment of the
commercial prospects of necitumumab can be made. However, it does
appear to have significant potential.

Necitumumab (proposed INN) is a monoclonal antibody and an antineoplastic. It binds to the epidermal growth factor receptor(EGFR).^[1] As of October 2009, two Phase III clinical trials are planned to investigate its effects on non-small cell lung carcinoma.^[2]^[3]

Possible Efficacy Of Lilly’s Necitumumab (IMC-11F8) In Lung Cancer Subset

18.4 2013

Eli Lilly announced yesterday their very preliminary and non-quantitative conclusions on the SQUIRE study, a 1093-patient Phase III trial of their anti-epidermal growth factor receptor (EGFR) antibody, necitumumab (IMC-11F8), against Stage IV squamous, non-small cell lung carcinoma (NSCLC).http://www.forbes.com/sites/davidkroll/2013/08/14/possible-efficacy-of-necitumumab-imc-11f8-in-squamous-nsclc-lung-cancer-subset/

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

New Drug Approvals

Yearly Archives: 2013

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

DR ANTHONY MELVIN CRASTO Ph.D

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Malaria Drug (Furamidine) to Treat Cancer

Pramlintide

Design and structure

FDA Approves Implanted Brain Stimulator for Epilepsy

EPROSARTAN MESYLATE

Big boost for Incyte as Jakafi shines in PhII

QbD: new Guidance from EMA and FDA

Chugai Pharma to commercialize Helsinn’s Anamorelin for anorexia-cachexia syndrome in Germany, France, Benelux, UK and Ireland

Anamorelin HCl

Mast Ischemia Drug Gets Orphan Drug Designation

MST-188 (purified poloxamer 188)

How MST-188 Works…

U.S. Food and Drug Administration Approves IMBRUVICA™ (ibrutinib) as a Single Agent for Patients with Mantle Cell Lymphoma

FDA OKs ‘Breakthrough’ Drug Imbruvica

Necitumumab

Possible Efficacy Of Lilly’s Necitumumab (IMC-11F8) In Lung Cancer Subset

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email

Yearly Archives: 2013

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Share this:

Design and structure

Share this:

Share this:

Share this:

Share this:

Share this:

Anamorelin HCl

Share this:

MST-188 (purified poloxamer 188)

How MST-188 Works…

Share this:

FDA OKs ‘Breakthrough’ Drug Imbruvica

Share this:

Possible Efficacy Of Lilly’s Necitumumab (IMC-11F8) In Lung Cancer Subset

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email