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Edoxaban, DU-176b
Daiichi Sankyo, APPROVED IN JAPAN as tosylate monohydrate salt in 2011 for the prevention of venous embolism in patients undergoing total hip replacement surgery
for synthesis see….http://www.sciencedirect.com/science/article/pii/S0968089613002642 Bioorganic & Medicinal Chemistry 21 (2013) 2795–2825, see s[pecific page 2808 for description ie 14/31 of pdf
WO 2010071121, http://www.google.com/patents/WO2010071121A1
WO 2007032498
N’-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide
NOV20, 2013
Daiichi Sankyo will file edoxaban on both sides of the Atlantic shortly after the bloodthinner proved as effective and safer than warfarin in a Phase III trial of patients with atrial fibrillation.
The company has presented data on edoxaban, a once-daily oral factor Xa inhibitor, at the American Heart Association meeting in Dallas, from a study involving 21,105 patients across 46 countries. The drug, evaluated in 60mg and 30mg doses, met its primary endpoint of non-inferiority compared to warfarin for the prevention of stroke or systemic embolic events in patients with non-valvular AF.http://www.pharmatimes.com/Article/13-11-20/Daiichi_Sankyo_anticoagulant_edoxaban_succeeds_in_Phase_III.aspx
Edoxaban (INN, codenamed DU-176b, trade name Lixiana) is an anticoagulant drug which acts as a direct factor Xa inhibitor. It is being developed by Daiichi Sankyo. It was approved in July 2011 in Japan for prevention of venous thromboembolisms (VTE) following lower-limb orthopedic surgery.[1]
In animal studies, edoxaban is potent, selective for factor Xa and has good oral bioavailability.[2]
Daichi Sankyo’s edoxaban tosilate is an orally administered
coagulation factor Xa inhibitor that was approved and launched
in Japan for the preventive treatment of venous thromboembolic
events (VTE) in patients undergoing total knee arthroplasty, total
hip arthroplasty, or hip fracture surgery. Edoxaban has been
shown to have a rapid onset of anticoagulant effect due to short
Tmax (1–2 h) after dosing and sustained for up to 24 h post-dose.
Marketed under the brand name Lixiana, it is currently in phase
III studies in the US for the prevention of stroke and systemic embolic
events in patients with atrial fibrillation (AF) and venous
thromboembolism (VTE).
Several Phase II clinical trials have been conducted, for example for thromboprophylaxis after total hip replacement[3] (phase III early results compare well to enoxaparin[4]), and for stroke prevention in patients with atrial fibrillation[5][6].Those papers follow similar recent major trials showing similar results for the other new factor Xa inhibitors, rivaroxaban and apixaban.
A large phase III trial showed that edoxaban was non inferior to warfarin in preventing recurrent venous thromboembolic events with fewer episodes of major bleeding.[7]
Drug formulation , lixiana, edoxaban tosylate monohydrate, CAS 912273-65-5, C24 H30 Cl N7 O4 S . C7 H8 O3 S . H2 O, 738.274
Citation ListPatent Literature
SIMILAR
OTHER SALTS
Edoxaban hydrochloride
CAS Number: 480448-29-1
Molecular Formula: C24H30ClN7O4S · HCl
Molecular Weight: 584.52 g.mol-1
Edoxaban is reported to be a member of the so-called “Xaban-group” and as such to be a low molecular inhibitor of the enzyme factor Xa, participating in the blood coagulation system. Therefore, edoxaban is classified as an antithrombotic drug and its possible medical indications are reported to be treatment of thrombosis and thrombosis prophylaxis after orthopaedic operations, such as total hip replacement, as well as for stroke prevention in patients with atrial fibrillation, the prophylaxis of the acute coronary syndrome and the prophylaxis after thrombosis and pulmonary embolism.
The IUPAC name for edoxaban is N’-(5-chloropyridin-2-yl)-N-[(15,2^,4S)-4- (dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[l ,3]thiazolo[5,4-c]pyridine-2- carbonyl)amino]cyclohexyl]oxamide. The chemical structure of edoxaban is shown in the formula (1) below:
formula ( 1 ) While Edoxaban is reported to be soluble in strongly acidic aqueous solutions, its solubility is considered to be very low in neutral or alkaline aqueous media. EP 2 140 867 A 1 claims an edoxaban-containing pharmaceutical composition comprising a water-swelling additive and/or a sugar alcohol. Further, it is alleged that compositions comprising lactose or cornstarch do not have good dissolution properties. The claimed pharmaceutical compositions in EP 2 140 867 Al are considered to show good dissolution properties in a neutral aqueous medium as well. Tablets comprising said composition were produced by wet granulation. However, it turned out that prior art pharmaceutical formulations comprising edoxaban being suitable for oral administration are still improvable with regards to dissolution rate and bioavailability. Further, stability and content uniformity of the known formulations could be improved. Further, due to the intolerance of many people to sugar alcohol(s), such as sorbitol, the use of sugar alcohol(s) should be avoided.
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]
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/
Ixabepilone, 219989-84-1 cas
(1R,5S,6S,7R,10S,14S,16S)-6,10-dihydroxy-1,5,7,
9,9-pentamethyl-14-[(E)-1-(2-methyl-1,3-thiazol-
4-yl)prop-1-en-2-yl]-17-oxa-13-azabicyclo[14.1.0]
heptadecane-8,12-dione
Ixabepilone (INN; also known as azaepothilone B, codenamed BMS-247550) is an epothilone B analog developed byBristol-Myers Squibb as a chemotherapeutic medication for cancer.
It is produced by Sorangium cellulosum.
It acts to stabilize microtubules. It is highly potent agent, capable of damaging cancer cells in very low concentrations, and retains activity in cases where tumor cells are insensitive to paclitaxel.
Ixabepilone is administered through injection, and is marketed under the trade name Ixempra.
patent approval expiry
| United States | 7312237 | 2004-08-21 | 2024-08-21 |
| United States | 6605599 | 1998-05-26 | 2018-05-26 |
| Applicant | Tradename | Generic Name | Dosage | NDA | Approval Date | Type | RLD | US Patent No. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Bristol Myers Squibb
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IXEMPRA KIT
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ixabepilone
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INJECTABLE;IV (INFUSION) | 022065 | Oct 16, 2007 | RX | Yes | RE41911*PED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Bristol Myers Squibb
|
IXEMPRA KIT
|
ixabepilone
|
INJECTABLE;IV (INFUSION) | 022065 | Oct 16, 2007 | RX | Yes | RE41393*PED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Bristol Myers Squibb
|
IXEMPRA KIT
|
ixabepilone
|
INJECTABLE;IV (INFUSION) | 022065 | Oct 16, 2007 | RX | Yes | 7,312,237*PED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Bristol Myers Squibb
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IXEMPRA KIT
|
ixabepilone
|
INJECTABLE;IV (INFUSION) | 022065 | Oct 16, 2007 | RX | Yes | 7,125,899*PED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patent No | Patent Expiry | patent use code |
|---|---|---|
| 6670384 | Jan 23, 2022 | U-959 |
| 6670384 | Jan 23, 2022 | U-960 |
| 6670384*PED | Jul 23, 2022 | |
| 7022330 | Jan 23, 2022 | U-958 |
| 7022330*PED | Jul 23, 2022 | |
| 7125899 | May 26, 2018 | U-957 |
| 7125899*PED | Nov 26, 2018 | |
| 7312237 | Aug 21, 2024 | U-965 |
| 7312237*PED | Feb 21, 2025 | |
| RE41393 | Feb 8, 2022 | U-961 |
| RE41393*PED | Aug 8, 2022 | |
| RE41911 | Sep 28, 2020 | U-961 |
| RE41911*PED | Mar 28, 2021 |
| Exclusivity Code | ExclusivityDate |
|---|---|
| NCE | Oct 16, 2012 |
| PED | Apr 18, 2015 |
| M-61 | Oct 18, 2014 |
| PED | Apr 16, 2013 |
| Exclusivity Code | ExclusivityDate |
|---|---|
| NCE | Oct 16, 2012 |
Ixabepilone, in combination with capecitabine, has demonstrated effectiveness in the treatment of metastatic or locally advanced breast cancer in patients after failure of an anthracycline and a taxane.
It has been investigated for use in treatment of non-Hodgkin’s lymphoma. In pancreatic cancer phase two trial it showed some promising results (used alone). Combination therapy trials are ongoing.
Ixabepilone is an anti cancer agent acting as a microtubule inhibitor, and which in particular are efficient in the treatment of cancer not reacting to other anti cancer agents, such as e.g. paclitaxel. Ixabepilone is marketed under the trade name Ixempra® and are approved for the treatment of aggressive metastatic or locally advanced breast cancer which not responding to the current prevailing chemotherapies.
Ixabepilone known under the CAS no. 219989-84-1 has the following structure:
Ixabepilone
Ixabepilone may be prepared from a starting material named epothilone B having the structural formula:
Epothilone B Ixabepilone as a compound is described in the USRE4191 1. USRE4191 1 furthermore disclose a process for synthesizing Ixabepilone.
The US 6,365,749 describes a process for making ixabepilone by reacting epothilone B with a palladium catalyst in the presence of a nucleophilic donor.
The USRE39356 do also describe a process for making Ixabepilone by reacting epothilone B with an azide donor agent and a reducing agent in the presence of a phase transfer catalyst and a palladium catalyst.
Ixabepilone is the treatment of metastatic and advanced breast cancer drugs.Ixabepilone as anticancer drugs alone or in combination with capecitabine (Capecitabine) in combination. October 16, 2007 approved for marketing by the FDA, trade name Ixempra, by the Bristol-Myers Squibb Company’s development.
Ixabepilone is an anti-mitotic drugs that are inhibitors of tubulin, the mechanism and paclitaxel (Taxol) the same class of drugs. Epothilone (Epothilone) by colistin (myxobacterium) Sorangium cellulosum fermentation of several macrolide metabolites in general. Anticancer activity in vitro experiments, epothilone A and epothilone B showed good activity, even in the paclitaxel-resistant cells also showed good activity. But its activity in vivo experiments in general, this is probably due to the body of the ester hydrolases that macrolide ring opening induced inactivation. In a series of epothilone derivatives activity test, it was found with the lactam bond instead of the original product of ester bonds – ixabepilone anticancer activity can be well retained.
Ixabepilone is epothilone B semi-synthetic derivatives. Epothilone B is a macrocyclic lactone, a hydroxyl moiety is allyl alcohol, the Pd catalyst can be obtained by ring-opening Pd complexes 1 , 1 received azide nucleophile attacking the anion generated with three azide product phosphorus reduction to give methyl amino acids 2 . Here we must point out that the attack was completely azide stereoselectivity, which is determined by two consecutive trans-attack lead, Pd (0)-trans lactone generate offensive allyl Pd complexes, to accept anti-azide anion type attack, to maintain the configuration of the product obtained. Amino acids 2 HoBt and EDCI generated by an amide bond to get ixabepilone.
IXEMPRA (ixabepilone) is a microtubule inhibitor belonging to a class of antineoplastic agents, the epothilones and their analogs. The epothilones are isolated from the myxobacterium Sorangium cellulosum. Ixabepilone is a semisynthetic analog of epothilone B, a 16-membered polyketide macrolide, with a chemically modified lactam substitution for the naturally existing lactone.
The chemical name for ixabepilone is (1S,3S,7S,10R,11S,12S,16R)-7,11dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]17-oxa-4-azabicyclo[14.1.0] heptadecane-5,9-dione, and it has a molecular weight of 506.7. Ixabepilone has the following structural formula:
 |
IXEMPRA (ixabepilone) for injection is intended for intravenous infusion only after constitution with the supplied DILUENT and after further dilution with a specified infusion fluid . IXEMPRA (ixabepilone) for injection is supplied as a sterile, non-pyrogenic, single-use vial providing 15 mg or 45 mg ixabepilone as a lyophilized white powder. The DILUENT for IXEMPRA is a sterile, non-pyrogenic solution of 52.8% (w/v) purified polyoxyethylated castor oil and 39.8% (w/v) dehydrated alcohol, USP. The IXEMPRA (ixabepilone) for injection and the DILUENT for IXEMPRA are co-packaged and supplied as IXEMPRA Kit.
….
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DR ANTHONY MELVIN CRASTO Ph.D
US-based clinical-stage biotechnology firm Advaxis has received orphan drug designation from the US Food and Drug Administration (FDA) for its lead drug candidate ADXS-HPV to treat human papillomavirus (HPV) associated head and neck cancer patients.
Advaxis’s cancer vaccine gets FDA orphan status for treatment of HPV-associated head and neck cancer
PRINCETON, N.J., Nov 05, 2013 (BUSINESS WIRE) — Advaxis, Inc., /quotes/zigman/23528806/delayed/quotes/nls/adxs ADXS +2.61% , a leader in developing the next generation of cancer immunotherapies, announced that it has been granted Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development (OOPD) for ADXS-HPV, its lead drug candidate, for the treatment of human papillomavirus (HPV)-associated head and neck cancer.
Orphan Drug Designation is granted to drug therapies intended to treat diseases or conditions that affect fewer than 200,000 people in the United States. Orphan Drug Designation entitles the sponsor to clinical protocol assistance with the FDA, as well as federal grants, tax credits, and potentially a seven year market exclusivity period.
“We are very pleased to have been granted an orphan drug designation for ADXS-HPV in this unmet medical need,” commented Dr. Robert Petit, Chief Scientific Officer of Advaxis. “Patients with head and neck cancer have limited treatment options and we hope to improve their survival by developing ADXS-HPV for this indication. We plan to initiate an additional Phase 1/2 study in early stage head and neck cancer for ADXS-HPV with a nationally recognized center of excellence, and we will continue the ongoing Phase 1 study being sponsored by the University of Liverpool and Aintree University Hospitals NHS Foundation Trust that is evaluating the safety and efficacy of ADXS-HPV when combined with standard chemotherapy and radiation treatment in patients with head and neck cancer.”
“Receiving orphan drug designation for ADXS-HPV in head and neck cancer is excellent news for a technology that may offer the potential to treat an indication with few therapy options, and, importantly, it helps define a clear path forward to registration,” commented Daniel J. O’Connor, President and Chief Executive Officer of Advaxis.
About Orphan Drug Designation
Under the Orphan Drug Act (ODA), the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for this type of disease or condition will be recovered from sales of the product. The benefits of orphan drug designation can be substantial and include federal grants, tax credits, and potentially a seven year market exclusivity period once the product is approved, provided that the product is first to market.
In order for a sponsor to obtain orphan designation for a drug or biological product, an application must be submitted to OOPD, and the designation approved. The approval of an application for orphan designation is based upon the information submitted by the sponsor. A drug that has obtained orphan designation is said to have “orphan status.” Each designation request must stand on its own merit. Sponsors requesting designation of the same drug for the same indication as a previously designated product must submit their own data in support of their designation request. The approval of an orphan designation request does not alter the standard regulatory requirements and process for obtaining marketing approval. Safety and efficacy of a compound must be established through adequate and well-controlled studies.
About ADXS-HPV
ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.
About Head and Neck Cancer
Cancer of the head and neck includes cancers arising from mucosa lining the oral cavity, oropharynx, hypopharynx, larynx, sinonasal tract, and nasopharynx. The most common histologic type observed is squamous cell carcinoma; therefore, the term “head and neck squamous cell carcinoma” (HNSCC) is frequently used to imply squamous cell carcinomas involving these anatomical sites. Excessive tobacco and alcohol are important risk factors for HNSCCs overall, but human papillomavirus (HPV) is now recognized as the causative agent in a subset of HNSCCs.
While the incidence of head and neck cancers that are linked to alcohol and tobacco use as the primary risk factor has fallen in the past three decades, a trend attributed to decreasing tobacco use in the United States, the incidence of HPV-associated head and neck cancer has been increasing. The increase was observed particularly among young individuals (<60 years of age), men, and Caucasians. Studies have shown that oral HPV infection is likely to be sexually acquired, as the increase in the incidence of HPV-associated head and neck cancers may be attributed to changing sexual practices. According to the World Health Organization’s Human Papillomavirus and Related Cancers in the World Summary Report 2010, HPV is associated with 20-50% of oral squamous cell carcinomas. HPV-associated head and neck cancer is growing at an epidemic rate in western countries; and occurs more frequently (3:1) in men than women. In the United States, the number of HPV-positive head and neck cancer cases has already equaled the number of cervical cancer cases.
About Advaxis, Inc.
Advaxis is a clinical-stage biotechnology company developing the next generation of immunotherapies for cancer and infectious diseases. Advaxis immunotherapies are based on a novel platform technology using live, attenuated bacteria that are bio-engineered to secrete an antigen/adjuvant fusion protein(s) that is designed to redirect the powerful immune response all human beings have to the bacterium to the cancer itself.
ADXS-HPV is currently being evaluated in four clinical trials for human papillomavirus (HPV)-associated cancers: recurrent/refractory cervical cancer (India), locally advanced cervical cancer (GOG/NCI U.S. study, Clinical Trials.gov Identifier NCT01266460), head & neck cancer (CRUK study, Clinical Trials.gov Identifier NCT01598792), and anal cancer (BrUOG study, Clinical Trials.gov Identifier NCT01671488). Advaxis has over 15 distinct immunotherapies in various stages of development, developed directly by Advaxis and through strategic collaborations with recognized centers of excellence such as: the University of Pennsylvania, the Georgia Regents University Cancer Center, Brown University Oncology Group, and others.
ADXS-HPV is currently in Phase 1/2 clinical development for recurrent/refractory and advanced cervical cancer, HPV caused head and neck cancers, and anal cancer.
Links to ADXS-HPV trials:
ADXS-HPV is an immunotherapy that is designed to target cells expressing the HPV gene E7. Expression of the E7 gene from high-risk HPV variants is responsible for the transformation of infected cells into dysplastic and malignant tissues. Eliminating these cells can eliminate the dysplasia or malignancy. ADXS-HPV is designed to infect antigen-presenting cells and direct them to generate a powerful, cellular immune response to HPV E7. The resulting cytotoxic Tcells infiltrate and attack the tumors while specifically inhibiting tumor Tregs and MDSCs in the tumors that are protecting it.
The American Cancer Society estimates that there will be about 12,340 newly diagnosed cervical cancer cases and 7,060 newly diagnosed cases of anal cancer in the U.S. in 2013.
In 2009, the CDC reported that about 45% of women aged 20 to 24 had HPV. HPV causes a number of different types of cancer. The same types of genital HPV that cause cervical cancer (HPV-16, HPV-18) cause about 8 out of 10 squamous cell anal cancers. In addition, nearly half of cancers of the vulva and about 7 out of 10 vaginal cancers are HPV-related. Some other genital cancers (cancers of the penis and urethra) and some head and neck cancers (mostly the throat, tongue, and tonsils) are also related to high-risk types of HPV. For additional information about HPV, please visit: http://www.cancer.org/.
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DR ANTHONY MELVIN CRASTO Ph.D
faldaprevir , 801283-95-4 cas no, BI-201335
(1R,2S)-1-{[(2S,4R)-4-[{8-bromo-7-methoxy-2-[2-(2-methylpropanamido)-1,3-thiazol-4-yl]quinolin-4-yl}oxy]-1-[(2S)-2-{[(cyclopentyloxy)carbonyl]amino}-3,3-dimethylbutanoyl]pyrrolidine-2-carboxamido]-2-ethenylcyclopropane-1-carboxylic acid
Molecular Formula: C40H49BrN6O9S
Molecular Weight: 869.82 g.mol-1
2 nd nov 2013
Boehringer Ingelheim today announced new data from its Phase III clinical trial programme, STARTVerso™, which evaluates faldaprevir* in combination with pegylated interferon and ribavirin (PegIFN/RBV). Patients with genotype-1 (GT-1) hepatitis C (HCV) who have not received previous treatment (treatment-naïve: STARTVerso™1&2),1 treatment-experienced patients (STARTVerso™3),2 and HIV co-infected patients (STARTVerso™4)3 participated in this study programme. The results from these and additional studies will be presented at the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), also known as The Liver Meeting®, taking place 1-5 November in Washington, D.C.
Faldaprevir (formerly BI 201335) is an experimental drug candidate for the treatment of hepatitis C. It is being developed byBoehringer-Ingelheim and is currently in Phase III trials.[1]
Faldaprevir is a hepatitis C virus protease inhibitor.
Faldaprevir is being tested in combination regimens with pegylated interferon and ribavirin, and in interferon-free regimens with other direct-acting antiviral agents including BI 207127.
Data from the SOUND-C2 study, presented at the 2012 AASLD Liver Meeting, showed that a triple combination of faldaprevir, BI 207127, and ribavirin performed well in HCV genotype 1b patients.[2] Efficacy fell below 50%, however, for dual regimens without ribavirin and for genotype 1a patients.
The following Compound 1):
(1)
wherein B is
; L° is MeO-; L1 is Br; and R2 is and having the chemical name: l-{ [4-[8-Bromo-2-(2-isopropylcarbamoyl-thiazol-4-yl)-7- methoxy-quinolin-4-yloxy]-l-(R)-(2-cyclopentyloxycarbonyl amino-3,3-(S)-dimethyl- butyryl)-pyrrolidine-(S)-2-carbonyl]-amino}-2-(S)-vinyl-cyclopropane-(R)-carboxylic acid, is known as a selective and potent inhibitor of the HCV NS3 serine protease and useful in the treatment of HCV infection. Compound (1) falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Patents RE 40,525, 7,514,557 and 7,585,845. Compound (1) is disclosed specifically as Compound # 1055 in U.S. Patent 7,585,845, and as Compound # 1008 in U.S. Patent 7,514,557. Compound (1), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference in their entirety. Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form, which can be prepared as described in U.S. Patent Application Publication No. 2010/0093792, also incorporated herein by reference. Data demonstrating the activity of Compound (1) as an inhibitor of the HCV NS3 serine protease and its corresponding demonstrated utility in the treatment of HCV infection in mono-infected patients, can be found in U.S. Patent 7,585,845, as well as in numerous publications presenting the preclinical characterization or clinical trial results with Compound (1). See, e.g., Sulkowski MS, et al, Hepatol (2009), Vol. 50, pg. 2A, Abtract LB3; Sulkowski MS, et al., J Hepatol (2010) Vol. 52, Supp. 1, pgs. S462-S463, Abstract 1190; Berg et al., Hepatol (2010), Vol. 52, Supp. SI, Abstract 804; and White PW, et al., Antimicrob Agents Chemother (2010) 54(11):4611-4618.
Combination therapy regimens directed to administering Compound (1) with an interferon- alpha and ribavirin for the treatment of HCV infection are described in U.S. Patent Application Publication Nos. 2010/0068182 and 2011/0268700.
HIV/HCV coinfected persons tend to have higher HCV viral loads and are less likely to clear the HCV spontaneously. The urgency for treatment of persons who are coinfected is greater than it is for those with HCV infection alone. The course of liver disease is more rapid in HIV/HCV-coinfected persons, including an approximately 2-fold increased risk of cirrhosis, more rapid progression to decompensated liver disease and increased risk for hepatocellular carcinoma (Graham CS, et al., Clin Infect Dis (2001 );33:562-569) .
Treatment of HCV might improve the tolerability of highly active antiretroviral therapy (HAART) because HCV infection increases the risk of mitochondrial toxicity and hepatotoxicity from HAART (Sulkowski MS, et al., JAMA (2000);283:74-80; Lafeuil!ade A, et al., Lancet (2001);357:280-281 ). Although there is much less published information on treatment outcomes in those who are HIV/HCV-coinfected than in HCV mono-infected patients, all accumulated data demonstrate that sustained virological response (SVR) and cure from HCV infection with pegylated interferon alpha and ribavirin is achieved in a substantially lower proportion of HIV/HCV coinfected patients when compared to HCV mono-infected patients. Factors associated with a poor treatment response (e.g., a high baseline HCV viral load, cirrhosis, and African American race) are present in a higher proportion of HIV/HCV coinfected populations, when compared to HCV monoinfected populations. It is not clear to what extent HIV infection itself diminishes the SVR rate, and to what extent advanced immunosuppression (e.g., CD4+ T lymphocyte count <200/mm3) further reduces response to HCV treatment (Toriani FJ, et al., N Engl J Med (2004);351(5): 438 -50; Nunez M, et al., ARHR (2007); 23(8):972-982).
Thus, there is a continuing high unmet need in the art for therapies that are effective against HCV in patients that are co-infected with HIV.
peptide soluble monomer], humanized monoclonal antibody;
gamma1 heavy chain [humanized VH (Homo sapiens IGHV3-23*04
(87.60%) -(IGHD)-IGHJ4*01) [8.8.5] (1-112) -Homo sapiens
IGHG1*01, CH3 K130>del (113-441)], (215-219′)-disulfide with
kappa light chain (1’-219’) [humanized V-KAPPA (Homo sapiens
IGKV2-30*01 (90.00%) -IGKJ1*01) [11.3.9] (1′-112′) -Homo sapiens
IGKC*01 (113′-219′)]; (221-221″:224-224″)-bisdisulfide dimer
neuroprotective agent
C6396H9922N1712O1996S42 955085-14-0
Heavy chain / Chaîne lourde / Cadena pesada
EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYSMSWVRQA PGKGLELVAQ 50
INSVGNSTYY PDTVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCASGD 100
YWGQGTLVTV SSASTKGPSV FPLAPSSKST SGGTAALGCL VKDYFPEPVT 150
VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK 200
PSNTKVDKKV EPKSCDKTHT CPPCPAPELL GGPSVFLFPP KPKDTLMISR 250
TPEVTCVVVD VSHEDPEVKF NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV 300
LTVLHQDWLN GKEYKCKVSN KALPAPIEKT ISKAKGQPRE PQVYTLPPSR 350
DELTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF 400
LYSKLTVDKS RWQQGNVFSC SVMHEALHNH YTQKSLSLSP G 441
Light chain / Chaîne légère / Cadena ligera
DVVMTQSPLS LPVTLGQPAS ISCRSSQSLI YSDGNAYLHW FLQKPGQSPR 50
LLIYKVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCSQSTHVP 100
WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150
VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200
VTHQGLSSPV TKSFNRGEC 219
Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro
Intra-H 22-96 139-195 256-316 362-420
22”-96” 139”-195” 256”-316” 362”-420”
Intra-L 23′-93′ 139′-199′
23”’-93”’ 139”’-199”’
Inter-H-L 215-219′ 215”-219”’
Inter-H-H 221-221” 224-224”
N-glycosylation sites / Sites de N-glycosylation / Posiciones de N-glicosilación
292, 292
The market for Alzheimer’s disease therapies is set to nearly triple between 2012 and 2022, despite increasing genericisation and the fact that few new product launches are expected during this time, according to new forecasts.
The key driver of growth in the AD market will be Eli Lilly’s anti-beta-amyloid monoclonal antibody solanezumab, the first potentially disease-modifying therapy (DMT) to launch for AD, according to the study, from Decision Resources. It reports that solanezumab is expected to launch in the seven major pharmaceutical markets – the US, France, Germany, Italy, Spain, the UK and Japan – starting in 2018 and that, by 2022, the drug is forecast to attain sales in excess of $5 billion in these markets.
More than 85% of solanezumab’s projected total use in 2022 will be in the mild AD market – the population in which the drug is currently being tested – followed by the pre-AD 1-2 years market segment, says the firm, which defines this latter population as those patients who will go on to develop overt AD within the next one to two years.
Solanezumab (proposed INN) is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector[1] for patients withAlzheimer’s disease.[2][3]
It binds to the amyloid-β peptides that make up the protein plaques seen in the brains of people with the disease.
2012 results of the EXPEDITION 1 & 2 phase 3 clinical trials were only mildly encouraging.[4][5][6] but were said to be the “first evidence that targeting the amyloid cascade can slow the progression of disease.”[7]
yellow coloured SOLANEZUMAB blocks beta amyloid from aa 16 to aa 25
Amyloid precursor protein (APP)
PRONUNCIATION nye vol’ ue mab
THERAPEUTIC CLAIM Treatment of cancer
CHEMICAL DESCRIPTION
A fully human IgG4 antibody blocking the programmed cell death-1 receptor (Medarex/Ono Pharmaceuticals/Bristol-Myers Squibb)
MOLECULAR FORMULA C6362H9862N1712O1995S42
MOLECULAR WEIGHT 143.6 kDa
SPONSOR Bristol-Myers Squibb
CODE DESIGNATION MDX-1106, BMS-936558
CAS REGISTRY NUMBER 946414-94-4
Bristol-Myers Squibb announced promising results from an expanded phase 1 dose-ranging study of its lung cancer drug nivolumab
Nivolumab (nye vol’ ue mab) is a fully human IgG4 monoclonal antibody designed for the treatment of cancer. Nivolumab was developed by Bristol-Myers Squibb and is also known as BMS-936558 and MDX1106.[1] Nivolumab acts as an immunomodulator by blocking ligand activation of the Programmed cell death 1 receptor.
A Phase 1 clinical trial [2] tested nivolumab at doses ranging from 0.1 to 10.0 mg per kilogram of body weight, every 2 weeks. Response was assessed after each 8-week treatment cycle, and were evaluable for 236 of 296 patients. Study authors concluded that:”Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use.”[3]
Phase III clinical trials of nivolumab are recruiting in the US and EU.[4]
The PD-1 blocking antibody nivolumab continues to demonstrate sustained clinical activity in previously treated patients with advanced non-small cell lung cancer (NSCLC), according to updated long-term survival data from a phase I trial.
Survival rates at one year with nivolumab were 42% and reached 24% at two years, according to the median 20.3-month follow up. Additionally, the objective response rate (ORR) with nivolumab, defined as complete or partial responses by standard RECIST criteria, was 17% for patients with NSCLC. Results from the updated analysis will be presented during the 2013 World Conference on Lung Cancer on October 29.
“Lung cancer is very difficult to treat and there continues to be a high unmet medical need for these patients, especially those who have received multiple treatments,” David R. Spigel, MD, the program director of Lung Cancer Research at the Sarah Cannon Research Institute and one of the authors of the updated analysis, said in a statement.
“With nivolumab, we are investigating an approach to treating lung cancer that is designed to work with the body’s own immune system, and these are encouraging phase I results that support further investigation in larger scale trials.”
In the phase I trial, 306 patients received intravenous nivolumab at 0.1–10 mg/kg every-other-week for ≤12 cycles (4 doses/8 week cycle). In all, the trial enrolled patients with NSCLC, melanoma, renal cell carcinoma, colorectal cancer, and prostate cancer.
The long-term follow up focused specifically on the 129 patients with NSCLC. In this subgroup, patients treated with nivolumab showed encouraging clinical activity. The participants had a median age of 65 years and good performance status scores, and more than half had received three or more prior therapies. Across all doses of nivolumab, the median overall survival was 9.9 months, based on Kaplan-Meier estimates.
In a previous update of the full trial results presented at the 2013 ASCO Annual Meeting, drug-related adverse events of all grades occurred in 72% of patients and grade 3/4 events occurred in 15%. Grade 3/4 pneumonitis related to treatment with nivolumab emerged early in the trial, resulting in 3 deaths. As a result, a treatment algorithm for early detection and management was developed to prevent this serious side effect.
Nivolumab is a fully human monoclonal antibody that blocks the PD-1 receptor from binding to both of its known ligands, PD-L1 and PD-L2. This mechanism, along with early data, suggested an associated between PD-L1 expression and response to treatment.
In separate analysis presented at the 2013 World Conference on Lung Cancer, the association of tumor PD-L1 expression and clinical activity in patients with NSCLC treated with nivolumab was further explored. Of the 129 patients with NSCLC treated with nivolumab in the phase I trial, 63 with NSCLC were tested for PD-L1 expression by immunohistochemistry (29 squamous; 34 non-squamous).
With 11 treatments in Phase I trials, 8 in Phase II, and 13 in Phase III, Bayer has a strong pipeline.
By far the most interest currently, given that the latest reports came out October 21st, is riociguat (BAY 63-2521),
which has had good news from its ongoing Phase III clinical trials of the treatment for pulmonary arterial hypertension, also known as PAH. PAH is a progressive condition that overburdens the heart.
Trials indicate subjects had improved heart function and could better tolerate physical exercise. Patients on riociguat improved their walking distance by 36 meters on average, while those on placebo showed no improvement.
Professor Hossein Ardeschir Ghofrani of University Hospital Giessen, the principal investigator, was quite pleased with the results and explained the value of the measurement. “The six-minute walk distance test is a well-validated clinical measure in patients with PAH, and therefore, the results of the PATENT-1 trial are encouraging. . .These data from the PATENT study suggest that riociguat may be a potential treatment option both for patients who have never been treated for PAH as well as for those who have received prior treatment.”
Hossein A. Ghofrani
Associate Professor of Internal Medicine,
MD (University of Giessen) 1995 Research interests: pulmonary hypertension, ischaemia-reperfusion, experimental therapeutics, clinical trials
http://www.uni-giessen.de/cms/fbz/fb11/forschung/graduierte/mbml/faculty
Although Bayer put forth no sales estimate for the treatment, analysts predicted 2017 sales from riociguat of $480 million
BAYER PIPELINE AS ON OCT 25 2013
phase 1
| Project | Indication |
|---|---|
| CDK-Inhibitor (BAY 1000394) | Cancer |
| Mesothelin-ADC (BAY 94-9343) | Cancer |
| PSMA Bi TE Antibody (BAY 2010112) | Cancer |
| PI3K-Inhibitor (BAY 1082439) | Cancer |
| FGFR2 Antibody (BAY 1179470) | Cancer |
| HIF-PH (BAY 85-3934) | Anemia |
| Partial Adenosine A1 Agonist(BAY 1067197) | Heart Failure |
| Vasopressin Receptor Antagonist(BAY 86-8050) | Heart Failure |
| sGC Stimulator (BAY 1021189) | Heart Failure |
| S-PRAnt (BAY 1002670) | Symptomatic uterine fibroids |
| BAY 1026153 | Endometriosis |
phase2
| Project | Indication |
|---|---|
| PI3K-Inhibitor (BAY 80-6946) | Cancer |
| Regorafenib | Cancer |
| Refametinib (MEK-Inhibitor) | Cancer |
| Radium-223-Dichloride | Cancer |
| Sorafenib | Additional Indications |
| MR-Antagonist (BAY 94-8862) | Congestive Heart Failure (CHF) |
| MR-Antagonist (BAY 94-8862) | Diabetic Nephopathy |
| Riociguat (sGC Stimulator) | Pulmonary Hypertension |
| Neutrophil Elastase Inhibitor(BAY 85-8501) | Bronchiectasis |
phase 3
| Project | Indication |
|---|---|
| Sorafenib | Breast Cancer |
| Sorafenib | Adjuvant HCC |
| Sorafenib | Adjuvant RCC |
| Regorafenib | HCC 2nd line |
| Rivaroxaban | Major Adverse Cardiac Events |
| Rivaroxaban | CHF and CAD |
| peg rFVIII(BAY 94-9027) | Hemophilia |
| Aflibercept | Myopic choroidal neovascularization (mCNV) |
| Aflibercept | Diabetic Macular Edema (DME) |
| LCS 16 | Contraception |
| Vaginorm | Vulvovaginal atrophy (VVA) |
| Sodium Deoxycholate | Submental fat removal |
| Cipro DPI | Lung infection |
| Tedizolid | Skin and Lung Infections |
| Amikacin Inhale | Gram-negative pneumonia |
Sorafenib tosylate
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
TEDIZOLID PHOSPHATE
Leverkusen, October 8, 2013 – Following the recent commercial introduction of five new drugs to address the medical needs of patients with various diseases, Bayer is now accelerating the development of further five promising drug candidates which are currently undergoing phase I and II clinical studies. The company today announced that it plans to progress these five new highly innovative drug candidates in the areas of oncology, cardiology, and women’s health into phase III clinical studies by 2015.
“Our Pharma research and development has done a tremendous job of bringing five new products to the market offering physicians and patients new treatment alternatives for serious diseases”, said Bayer CEO Dr. Marijn Dekkers. “Following our mission statement ‘Science For A Better Life’, the five chosen further drug candidates all have the potential to impact the way diseases are treated for the benefit of patients.”
Bayer CEO Dr. Marijn Dekkers
“Our research and development activities are strongly focused on areas where treatment options are not available today or where true breakthrough innovations are missing”, said Prof. Andreas Busch, member of the Bayer HealthCare Executive Committee and Head of Global Drug Discovery at Bayer HealthCare. “Our drug development pipeline holds a number of promising candidates which we want to bring to patients who need them urgently”, said Kemal Malik, member of the Bayer HealthCare Executive Committee, Chief Medical Officer and Head of Pharmaceutical Development at Bayer HealthCare. “Furthermore we are continuing to expand the range of indications for all our recently launched products Xarelto, Stivarga, Xofigo, Riociguat as well as Eylea and further refine the profile of these drugs in specific patient populations.”
Cl 223Ra Cl
Xofigo
https://newdrugapprovals.wordpress.com/2013/09/21/xofigo-injection-recommended-for-approval-in-eu/
The five mid-stage candidates have been selected for accelerated development based on positive “proof-of-concept” data from early clinical studies. Three of them are development compounds in the area of cardiology or the cardio-renal syndrome: Finerenone (BAY 94-8862) is a next generation oral, non-steroidal Mineralocorticoid Receptor antagonist which blocks the deleterious effects of aldosterone. Currently available steroidal MR antagonists have proven to be effective in reducing cardiovascular mortality in patients with heart failure but have significant side effects that limit their utilization. Finerenone is currently in clinical Phase IIb development for the treatment of worsening chronic heart failure, as well as diabetic nephropathy.
Finerenone (BAY 94-8862)
The second drug candidate in the area of cardiology is an oral soluble guanylate cyclase (sGC) stimulator (BAY 1021189). The start of a Phase IIb study in patients with worsening chronic heart failure is expected later this year.
For the cardio-renal syndrome, a Phase IIb program with the investigational new drug Molidustat (BAY 85-3934) is under initiation in patients with anemia associated with chronic kidney disease and/or end-stage renal disease. Molidustat is a novel inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) which stimulates erythropoietin (EPO) production and the formation of red blood cells. Phase I data have shown that inhibition of HIF-PH by Molidustat results in an increase in endogenous production of EPO.
Molidustat (BAY 85-3934)
In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.
Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.
Initiation of further studies with recently launched products
Bayer has successfully launched five new pharmaceutical products, namely Xarelto™, Stivarga™, Xofigo™, Eylea™, and Riociguat, which has very recently been approved in Canada under the trade name Adempas™.
Regorafenib, stivarga
Bayer’s Eylea (aflibercept),
https://newdrugapprovals.wordpress.com/2013/06/01/lucentis-rival-one-step-away-from-nhs-approval/
Xarelto has been approved globally for five indications across seven distinct areas of use, allowing doctors to treat patients in a greater variety of venous and arterial thromboembolic conditions than any other novel oral anticoagulant. The company continues to study the use of Xarelto for the treatment of further cardiovascular diseases. Ongoing clinical Phase III studies include COMPASS and COMMANDER-HF. The COMPASS study will assess the potential use of Xarelto in combination with aspirin, or as a single treatment to prevent major adverse cardiac events (MACE) in nearly 20,000 patients with atherosclerosis related to coronary or peripheral artery disease. The COMMANDER-HF study will evaluate the potential added benefit of Xarelto in combination with single or dual-antiplatelet therapy to help reduce the risk of death, heart attack and stroke in approximately 5,000 patients with chronic heart failure and coronary artery disease, following hospitalization for exacerbation of their heart failure.
In order to answer medically relevant questions for specific patient populations Bayer has initiated a range of additional Xarelto studies in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent placement (PIONEER-AF-PCI), cardioversion (X-VERT) or an AF ablation procedure (VENTURE-AF).
As an extension to the Xarelto clinical trial programme, a number of real-world studies are designed to observe and further evaluate Xarelto in everyday clinical practice. These include the XAMOS study of more than 17,000 orthopaedic surgery patients, which confirmed the clinical value of oral, once-daily Xarelto in routine clinical practice in adults following orthopaedic surgery of the hip or knee. XANTUS is designed to collate data on real-world protection with Xarelto in over 6,000 adult patients in Europe with non-valvular AF at risk of stroke while XANAP is designed to collate data on real-world protection with Xarelto in over 5,000 adult patients in Europe and Asia with non-valvular AF at risk of stroke. XALIA will generate information from over 4,800 patients treated for an acute DVT with either Xarelto or standard of care.
In the area of oncology, Stivarga has been approved in 42 countries for use against metastatic colorectal cancer that is refractory to standard therapies, and additionally for gastrointestinal stromal tumor (GIST) in the US and Japan. Bayer is now planning to assess Stivarga in earlier stages of colorectal cancer as well as other cancer types. A Phase III trial in patients with colorectal cancer after resection of liver metastases is currently under initiation. Based on early clinical data Bayer has also initiated a Phase III study in liver cancer in patients who have progressed on sorafenib treatment.
Furthermore, the anti-cancer drug Xofigo (radium 223 dichloride) is a first-in-class alpha-pharmaceutical which is designed for use in prostate cancer patients with ‘bone metastases’ (secondary cancers in the bone) to treat the cancer in the bone and to help extend their lives. Xofigo is approved in the US for the treatment of patients with advanced castrate-resistant prostate cancer with symptomatic bone metastases. In addition, the European CHMP recently gave a positive opinion for radium 223 dichloride for the same use. The decision of the European Commission on the approval is expected in the fourth quarter of 2013.
Based on the excellent Phase III results for Xofigo in patients with castration resistant prostate cancer and symptomatic bone metastases Bayer is looking to expand the use of Xofigo to earlier stages of the disease, and plans to initiate a Phase III study in combination with the novel anti-hormonal agent abiraterone. In addition, early stage signal-generating studies in other cancer forms where bone metastases are important causes of morbidity and mortality are planned.
In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.
In the area of ophthalmology, Eylea (aflibercept solution for injection) is already approved in Europe and several additional countries for the treatment of neovascular (wet) age-related macular degeneration and for macular edema following central retinal vein occlusion. In September, Bayer HealthCare and Regeneron Pharmaceuticals presented data of the two phase III clinical trials VIVID-DME and VISTA-DME of VEGF Trap-Eye for the treatment of diabetic macular edema (DME) at the annual meeting of the Retina Society in Los Angeles and at the EURetina Congress in Hamburg, Germany. Both trials achieved the primary endpoint of significantly greater improvements in best-corrected visual acuity from baseline compared to laser photocoagulation at 52 weeks. Bayer plans to submit an application for marketing approval for the treatment of DME in Europe in 2013.
About Bayer HealthCare
The Bayer Group is a global enterprise with core competencies in the fields of health care, agriculture and high-tech materials. Bayer HealthCare, a subgroup of Bayer AG with annual sales of EUR 18.6 billion (2012), is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany. The company combines the global activities of the Animal Health, Consumer Care, Medical Care and Pharmaceuticals divisions. Bayer HealthCare’s aim is to discover, develop, manufacture and market products that will improve human and animal health worldwide. Bayer HealthCare has a global workforce of 54,900 employees (Dec 31, 2012) and is represented in more than 100 countries. More information at www.healthcare.bayer.com.
 |
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|---|---|
http://www.ama-assn.org/resources/doc/usan/ixekizumab.pdf
USAN IXEKIZUMAB
PRONUNCIATION ix” e kiz’ ue mab
THERAPEUTIC CLAIM Treatment of autoimmune diseases
CHEMICAL NAMES
1. Immunoglobulin G4, anti-(human interleukin 17A) (human monoclonal LY2439821γ4-chain), disulfide with human monoclonal LY2439821 κ-chain, dimer
2. Immunoglobulin G4, anti-(human interleukin-17A (IL-17, cytotoxic
T-lymphocyte-associated antigen 8)); humanized mouse monoclonal LY2439821 des-Lys446-[Pro227]γ4 heavy chain {H10S>P,CH3107K>-} (133-219′)-disulfide with humanized mouse monoclonal LY2439821 κ light chain, dimer (225-225”:228-228”)-bisdisulfide
MOLECULAR FORMULA C6492H10012N1728O2028S46
MOLECULAR WEIGHT 146.2 kDa
SPONSOR Eli Lilly and Co.
CODE DESIGNATION LY2439821
CAS REGISTRY NUMBER 1143503-69-8
Ixekizumab is a humanized monoclonal antibody used in the treatment of autoimmune diseases.[1]
Ixekizumab was developed by Eli Lilly and Co.
more info
Inflammation represents a key event of many diseases, such as psoriasis, inflammatory bowel diseases, rheumatoid arthritis, asthma, multiple sclerosis,
atherosclerosis, cystic fibrosis, and sepsis. Inflammatory cells, such as neutrophils, eosinophils, basophils, mast cells, macrophages, endothelial cells, and platelets, respond to inflammatory stimuli and foreign substances by producing bioactive mediators. These mediators act as autocrines and paracrines by interacting with many cell types to promote the inflammatory response. There are many mediators that can promote inflammation, such as cytokines and their receptors, adhesion molecules and their receptors, antigens involved in lymphocyte activation, and IgE and its receptors. [0004] Cytokines, for example, are soluble proteins that allow for communication between cells and the external environment. The term cytokines includes a wide range of proteins, such as lymphokines, monokines, interleukins, colony stimulating factors, interferons, tumor necrosis factors, and chemokines. Cytokines serve many functions, including controlling cell growth, migration, development, and differentiation, and mediating and regulating immunity, inflammation, and hematopoiesis. Even within a given function, cytokines can have diverse roles. For example, in the context of mediating and regulating inflammation, some cytokines inhibit the inflammatory response (anti-inflammatory cytokines), others promote the inflammatory response (pro-inflammatory cytokines). And certain cytokines fall into both categories, i.e., can inhibit or promote inflammation, depending on the situation. The targeting of proinflammatory cytokines to suppress their natural function, such as with antibodies, is a well-established strategy for treating various inflammatory diseases.
Many inflammatory diseases are treated by targeting proinflammatory cytokines with antibodies. Most (if not all) of the anti-proinflammatory cytokine antibodies currently on the market, and those currently in clinical trials, are of the IgG class. See, for example, Nature Reviews, vol. 10, pp. 301-316 (2010); Nature Medicine, vol. 18, pp. 736-749 (2012); Nature Biotechnology, vol. 30, pp. 475-477 (2012); Anti-Inflammatory & Anti- Allergy Agents in Medicinal Chemistry, vol. 8, pp. 51-71 (2009);
FlOOO.com/Reports/Biology/content/1/70, F 1000 Biology Reports, 1 :70 (2009); mAbs 4: 1, pp. 1-3 (2012); mAbs 3: 1, pp. 76-99 (2011); clinicaltrials.gov (generally), and
clinicaltrialsregister.eu/ (generally). These IgG antibodies are administered systemically and thus are often associated with unwanted side effects, which can include one or more of, for example, infusion reactions and immunogenicity, hypersensitivity reactions,
immunosuppression and infections, heart problems, liver problems, and others. Additionally the suppression of the target cytokines at non-diseased parts of the body can lead to unwanted effects.
In an attempt to reduce side effects associated with systemic treatment and to eliminate the inconvenience and expense of infusions, an article proposed an oral anti-TNF therapy that could be useful in treating Crohn’ s disease. Worledge et al. “Oral Administration of Avian Tumor Necrosis Factor Antibodies Effectively Treats Experimental Colitis in Rats.” Digestive Diseases and Sciences 45(12); 2298-2305 (December 2000). This article describes immunizing hens with recombinant human TNF and an adjuvant, fractionating polyclonal yolk antibody (IgY, which in chickens is the functional equivalent to IgG), and administering the unformulated polyclonal IgY (diluted in a carbonate buffer to minimize IgY acid hydrolysis in the stomach) to rats in an experimental rodent model of colitis. The rats were treated with 600mg/kg/day of the polyclonal IgY. The uses of animal antibodies and polyclonal antibodies, however, are undesirable.
In a similar attempt to avoid adverse events associated with systemic administration, another group, Avaxia Biologies Inc., describes a topical (e.g., oral or rectal) animal-dervied polyclonal anti-TNF composition that could be useful in treating
inflammation of the digestive tract, such as inflammatory bowel disease. WO2011047328. The application generally states that preferably the polyclonal antibody composition is prepared by immunizing an animal with a target antigen, and the preferably the polyclonal antibody composition is derived from milk or colostrum with bovine colostrums being preferred (e.g., p. 14). The application also generally states that the animal derived polyclonal antibodies could be specific for (among other targets) other inflammatory cytokines (e.g., pp. 6-7). This application describes working examples in which cows were immunized with murine TNF and the colostrum was collected post-parturition to generate bovine polyclonal anti-TNF antibodies (designated as AVX-470). The uses of animal-derived antibodies and polyclonal antibodies, however, are undesirable.
IgA molecular forms have been proposed as treatments for various diseases, most notably as treatments for pollen allergies, as treatments against pathogens, and as treatments for cancer.
For example, one article describes anti-AmbCtl (a ragweed pollen antigen) humanized monomelic IgA and dimeric IgA antibodies made in murine cells (NSO and Sp2/0 cells). The dimeric IgA contains a mouse J-chain. The article proposes that the antibodies may be applied to a mucosal surface or the lower airway to inhibit entry of allergenic molecules across the mucosal epithelium and therefore to prevent the development of allergic response. Sun et al. “Human IgA Monoclonal Antibodies Specific for a Major Ragweed Pollen Antigen.” Nature Biotechnology 13, 779-786 (1995).
Several other articles propose the use of IgA antibodies as a defense against pathogens.
Two articles proposed the use of an anti-streptococcal antigen I II secretory IgA-G hybrid antibody. Ma et al. “Generation and Assembly of Secretory Antibodies in Plants.” Science 268(5211), 716-719 (May 1995); Ma et al. “Characterization of a
Recombinant Plant Monoclonal Secretory Antibody and Preventive Immunotherapy in Humans.” Nature Medicine 4(5); 601-606 (May 1998). The hybrid antibody contains murine monoclonal kappa light chain, hybrid Ig A-G heavy chain, murine J- Chain, and rabbit secretory component. The antibody was made by successive sexual crossing between four transgenic N. tabacum plants and filial recombinants to form plant cells that expressed all four protein chains simultaneously. The parent antibody (the source of the antigen binding regions, is identified as the IgG antibody Guy’s 13. The group proposes that although slgA may provide an advantage over IgG in the mucosal environment, such is not always the case (1998 Ma at p. 604, right column).
A related article identifies the anti-streptococcal antigen I/II secretory IgA-G hybrid antibody, which was derived from Guy’s 13 IgA, as CaroRx. Wycoff. “Secretory IgA Antibodies from Plants.” Current Pharmaceutical Design 10(00); 1-9 (2004). Planet Biotechnology Inc. This related article states that the CaroRx antibody was designed to block adherence to teeth of the bacteria that causes cavities. Apparently, the CaroRx antibody was difficult to purify; the affinity of Protein A for the murine Ig domain was too low and protein G was necessary for sufficient affinity chromatography. Furthermore, the article states that several other chromatographic media had shown little potential as purification steps for the hybrid slgA-G from tobacco leaf extracts. The article also indicates that the authors were unable to control for human-like glycosylation in tobacco, but that such was not a problem because people are exposed to plant glycans every day in food without ill effect.
WO9949024, which lists Wycoff as an inventor, Planet Biotechnology Inc. as the applicant, describes the use of the variable regions of Guy’s 13 to make a secretory antibody from tobacco. The application contains only two examples – the first a working example and the second a prophetic example. Working Example 1 describes the transient production of an anti-S. mutans SA I/III (variable region from Guy’s 13) in tobacco. The tobacco plant was transformed using particle bombardment of tobacco leaf disks. Transgenic plants were then screened by Western blot “to identify individual transformants expressing assembled human slgA” (p. 25). Prophetic Example 2 states that in a transformation system for Lemna gibba (a monocot), bombardment of surface-sterilized leaf tissue with DNA- coated particles “is much the same as with” tobacco (a dicot). The prophetic example also stops at screening by immunoblot analysis for antibody chains and assembled slgA, and states that the inventors “expect to find fully assembled slgA.” [0014] Another article proposed the use of an anti-RSV glycoprotein F IgA antibodies (mlgA, dlgA, and slgA). Berdoz et al. “In vitro Comparison of the Antigen-Binding and Stability Properties of the Various Molecular Forms of IgA antibodies Assembled and Produced in CHO Cells.” Proc. Natl. Acad. Sci. USA 96; 3029-3034 (March 1999). The slgA antibody was made in CHO cells sequentially transfected with chimeric heavy and light chains, human J-Chain, and human secretory component, respectively. Single clones were generated to express the mlgA (clone 22), the dlgA (clone F), and the slgA (clone 6) (p. 3031).
Still other articles proposed, for example: (1) anti-HSV mlgA made in maize (Karnoup et al. Glycobiology 15(10); 965-981 (May 2005)) (which states that at that time there had been little success in the application of IgA class antibodies to therapeutic use because of the difficulty in producing the dimeric form in mammalian cells at economic levels); (2) anti-C. difficile toxin A chimeric mouse-human monomeric and dimeric IgA made in CHO cells (Stubbe et al. Journal of Immunology 164; 1952-1960 (2000)); (3) anti-N. meningitidis chimeric IgA antibodies were produced in BHK cells cotransfected with human J-Chain and/or human secretory component (Vidarsson et al., Journal of Immunology 166; 6250-6256 (2001)); (4) mti-Pseudomonas aeruginosa 06 lipopolysaccharide chimeric mouse/human mlgAl made in CHO cells (Preston et al. Infection and Immunity 66(9); 4137- 4142 (September 1998)); (5) anti-Plasmodium mlgA made in CHO cells (Pleass et al. Blood 102(13); 4424-4429 (December 2003)) (which states that unlike their parental mouse IgG antibodies, the mlgA antibodies failed to protect against parasitic challenge in vivo); and (5) ^^-Helicobacter pylori urease subunit A slgA and dlgA (Berdoz et al. Molecular
Immunology 41(10); 1013-1022 (August 2004)). [0016] For a review article discussing passive and active protection against pathogens at mucosal surfaces, see Corthesy. “Recombinant Immunoglobulin A: Powerful Tools for Fundamental and Applied Research.” Trends in Biotechnology 20(2); 65-71 (February 2002).
Still other articles propose the use of IgA antibodies as a treatment for cancer.
For example, one article describes a Phase la trial of a muring anti-transferrin receptor IgA antibody (Brooks et al. “Phase la Trial of Murine Immunoglobulin A
Antitransferrin Receptor Antibody 42/6.” Clinical Cancer Research 1(11); 1259-1265 (November 1995)). Another article describes a human anti-Ep-CAM mIgA made in BHK (baby hamster kidney) cells (Huls et al. “Antitumor Immune Effector Mechanisms Recruited by Phase Display-Derived Fully Human IgGl and IgAl Monoclonal Antibodies.” Cancer Research 59; 5778-5784 (November 1999)). Still another article describes an anti-HLA Class II chimeric mIgA antibody made in BHK cells (Dechant et al. “Chimeric IgA Antibodies Against HLA Class II Effectively Trigger Lymphoma Cell Killing.” Blood 100(13); 4574- 4580 (December 2002)). Yet other articles describe anti-EGFR mIgA or dlgA antibodies made in CHO, including Dechant et al. “Effector Mechanisms of Recombinant IgA
Antibodies Against Epidermal Growth Factor Receptor.” Journal of Immunology 179; 2936- 2943 (2007), Beyer et al. “Serum- Free Production and Purification of Chimeric IgA
Antibodies.” Journal of Immunology 346; 26-37 (2009) (stating that as of 2009, IgA antibodies have not been commercially explored for problems including lack of production and purification methods), and Lohse et al. “Recombinant Dimeric IgA Antibodies Against the Epidermal Growth Factor Receptor Mediate Effective Tumor Cell Killing.” Journal of Immunology 186; 3770-3778 (February 2011).
For a review article on anti-cancer IgA antibodies, see Dechant et al. “IgA antibodies for Cancer Therapy. ” Critical Reviews in Oncology/Hematology 39; 69-77 (2001); states that compared with infectious diseases, the role of IgA in cancer immunotherapy is even less investigated).
IL17 and IFN-garama inhibition for the treatment of autoimmune inflammation
The IL-17 family of cytokines has been associated with the pathogenesis of autoimmune diseases and is generally blamed for the pathogenic symptoms of autoimmune inflammation. Overexpression of IL-17 is a hallmark for autoimmune diseases like rheumatoid arthritis, systemic lupus erythematomatosus, inflammatory bowel disease, multiple sclerosis, and psoriasis (Yao Z et. al., J Immunol, 155(12), 1995, 5483-6. Chang S H, et.al, Cytokine, 46, 2009, 7-11; Hisakata Yamada et.al, Journal of Inflamm. Res., 3, 2010, 33-44)).
The IL-17 cytokine family comprises six members, out of which IL-17 A and IL-17F are the best characterized. IL-17A and IL-17F exist as homo- as well as as heterodimers (IL-17AA, IL-17AF, IL-17FF). IL-17A and IL-17F are clearly associated with inflammation (Gaffen S H, Cytokine, 43, 2008, 402-407; Torchinsky M B et al, Cell. Mol. Life Sci., 67, 2010, 1407- 1421).
The secretion of IL-17 is predominantly caused by a specific subtype of T helper cells termed TH-17 cells. IL-23, TGFp and IL-6 were shown to be important factors leading to conversion of nai‘ve CD4+ T-cells to THl 7 cells. It was also reported that TGF and IL-6 potently induce in synergy THl 7 differentiation. Important transcription factors for the secretion of IL-17 from TH17 cells are RORyt and STAT3 (IvanovJ et.al. Cell 126, 2006, 1121-1133). IL-17 induces pro-inflammatory cytokines (IL-6, TNF- and IL-lb) and Chemokines (CXCL1,GCP-2,CXCL8 or IL-8,CINC,MCP-1). It increases the production of nitric oxide prostaglandin E2 and matrix-metalloproteinases. As a consequence of these events neutrophil infiltration, tissue damage and chronic inflammation occurs (PECK A et.al, Clin Immunol., 132(3), 2009, 295-304).
Before the recognition of the importance of IL-17 in autoimmune inflammation, IFN-gamma derived from THl cells was believed to be an important cytokine that drives autoimmune disorders (Takayanagi H et. al. Nature, 408, 2000, 600-605. Huang W. et. al. Arthritis Res. Ther., 5, 2002, R49-R59) The secretion of IFN-gamma is a key feature of the THl effector cell lineage and the secretion is regulated by the transcription factors T-bet and STAT4 (Bluestone JA et. al. Nat Rev Immunol, 11, 2009, 811-6). Infiltration of activated T-cells and elevation of M-CSF, IL-10 and TNF support this notion (Yamanda H et.al Ann. Rheu. Dis., 67, 2008, 1299-1304; Kotake S et.al. Eur. J. Immunol, 35, 2005, 3353-3363).
Recently, a more complex situation was proposed, where hybrid TH17/TH1 cells induced by IL-23 and IL-6 in concert with IL-1 secrete IL-17 and IFN-gamma. These cells are under the control of the transcription factors RORyt and T-bet, confirming the notion, that these are true hybrids of THl and THl 7 cells. It was also demonstrated that these double producing cells are the pathogenic species in IBD and EAE (Buonocore S et.al. Nature, 464, 2010, 1371-5; Ghoreshi K. et. al. Nature, 467, 2010, 967-971).
Compounds which target and suppress both IL-17 and IFN-gamma are predisposed for the treatment of autoimmune disorders.
The effectiveness of blocking IL-17 signaling as therapeutic treatment in autoimmune diseases has already been proven in clinical trials with e.g. monoclonal antibodies against IL- 17A (AIN457, secukinumab; Ly2439821,ixekizumab; RG4934) and/or the IL-17 receptor IL- 17RA (AMG827, brodalumab).
Positive results have been reported for the treatment of rheumatoid arthritis, psoriasis and uveitis (Hueber W et al, Sci. Transl. Med., 2, 2010, 52ra72, DOI: 10.1126/scitranslmed.3001107; van den Berg W B e/ al, Nat. Rev. Rheumatol, 5, 2009, 549-553), ankylosing spondylitis and spondyloarthritides (Song I-H et al, Curr. Opin. Rheumatol., 23, 2011, 346-351).
Secukinumab is currently under investigation in clinical trials for psoriatic arthritis, Behcet disease, uveitits, inflammatory bowel disease, Crohn’s disease, multiple sclerosis (Kopf M et al., Nat. Rev. Drug Disc, 9, 2010, 703-718; Song I-H et al, Curr. Opin. Rheumatol., 23, 2011, 346-351).
Brodalumab, Ixekizumab and RG4934 are currently in clinical trials for the treatment of rheumatoid arthritis, psoriasis and/or psoriatic arthritis (Kopf M et al, Nat. Rev. Drug Disc, 9, 2010, 703-718; clinicaltrials.gov; Medicines in development for skin diseases, 201 1, published by PhRMA, www .phrma. com) .
With regard to blocking of IFN-gamma signaling as therapeutic treatment in autoimmune diseases, the IFN-gamma-specific monoclonal antibody AMG811 is currently under clinical investigations for the treatment of systemic lupus erythematosus (Kopf M et al., Nat. Rev. Drug Disc, 9, 2010, 703-718).
ALCAFTADINE
Alcaftadine is used to prevent eye irritation brought on by allergic conjunctivitis. It is a H1histamine receptor antagonist.
It was approved by the U.S. Food and Drug Administration in 2010 under the trade name Lastacaft.
| Active Ingredient | Form | Dosage | Drug Type | Application | Product | |
|---|---|---|---|---|---|---|
| ALCAFTADINE | SOLUTION/DROPS; OPHTHALMIC | 0.25% | RX | 022134 | 001 |
There are 1 patent(s) protecting ALLERGAN’s LASTACAFT.
The last patent expires on 2013-11-21.
| Patent | Expiration | |
|---|---|---|
| US5468743 | Imidazo[2,1-b]benzazepine derivatives, compositions and method of use
The present invention is concerned with novel imidazo[2, 1-b][3]benzazepines of formula ##STR1## the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein each of the dotted lines independently represents an optional bond; R.sup.1 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.2 represents hydrogen, halo, C.sub.1-4 alkyl or C.sub.1-4 alkyloxy; R.sup.3 represents hydrogen, C.sub.1-4 alkyl, ethenyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyl substituted with hydroxycarbonyl or C.sub.1-4 alkyloxycarbonyl, hydroxyC.sub.1-4 alkyl, formyl or hydroxycarbonyl; R.sup.4 represents hydrogen, C.sub.1-4 alkyl, hydroxyC.sub.1-4 alkyl, phenyl or halo; R.sup.5 represents hydrogen, C.sub.1-4 alkyl or halo; L represents hydrogen; C.sub.1-6 alkyl; C.sub.1-6 alkyl substituted with one substituent selected from the group consisting of hydroxy, halo, C.sub.1-4 alkyloxy, hydroxycarbonyl, C.sub.1-4 alkyloxycarbonyl, C.sub.1-4 alkyloxycarbonyl-C.sub.1-4 alkyloxy, hydroxycarbonylC.sub.1-4 alkyloxy, C.sub.1-4 alkyloxycarbonylamino, C.sub.1-4 alkylaminocarbonyl, C.sub.1-4 alkylaminocarbonylamino, C.sub.1-4 alkylaminothiocarbonylamino, aryl, aryloxy and arylcarbonyl; C.sub.1-6 alkyl substituted with both hydroxy and aryloxy; C.sub.3-6 alkenyl; C.sub.3-6 alkenyl substituted with aryl; or, L represents a radical of formula –Alk–Y–Het.sup.1 (a-1),–Alk–NH–CO–Het.sup.2 (a-2)or –Alk–Het.sup.3 (a-3); provided that 6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine is ecxluded, which are useful antiallergic compounds.Compositions comprising said compounds, methods of using and processes for preparing the same.
|
2013-11-21 |
Exclusivity is marketing rights granted by the FDA to the ALLERGAN.
Exclusivity ends on 2015-07-28.
| Date | Supplement No. | Action | Documents |
|---|---|---|---|
| 2010-07-28 | 000 | Approval |
New Drug Approvals 
