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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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AbbVie’s glioblastoma multiforme therapy receives orphan drug designation


ABT-414 is in phase I/II clinical development at AbbVie for the treatment of squamous cell carcinoma. The product is also in early clinical development for the treatment of glioblastoma multiforme.

In 2014, orphan drug designation was received in the U.S. and E.U. by AbbVie for the treatment of glioblastoma multiforme.

EGFR antibody-drug conjugate (cancer), Abbott; ABT-414; EGFR antibody-drug conjugate (cancer), AbbVie; EGFR-ADC (cancer), AbbVie; ABT-806-MMAF conjugate; anti-EGFR antibody-MMAF conjugate, AbbVie; EGFR-ADC (cancer), Abbott

 

AbbVie’s glioblastoma multiforme therapy receives orphan drug designation
AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.

AbbVie has obtained orphan drug designation from the European Medicines Agency (EMA) and the US FDA for its anti-epidermal growth factor receptor monoclonal antibody drug conjugate, ABT-414, as a treatment for glioblastoma multiforme.

read at

 

http://www.pharmaceutical-technology.com/news/newsabbvies-glioblastoma-multiforme-therapy-receives-orphan-drug-designation-4335836?WT.mc_id=DN_News

 

AbbVie’s ABT-414 Receives FDA and EMA Orphan Drug Designation

AbbVie announced that the EMA and the FDA have granted orphan drug status to its investigational compound ABT-414, an anti-epidermal growth factor receptor antibody drug conjugate. It is currently being evaluated for safety and efficacy in patients with glioblastoma multiforme. Glioblastoma multiforme is the most common and most aggressive type of malignant primary brain tumor. Each year in the United States and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma multiforme, which has a five-year survival rate of approximately 4 percent.

“The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options,” said Gary Gordon, M.D., vice president, oncology clinical development, AbbVie. “We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I program.” Read the press release

 

 

AbbVie oncology clinical development vice-president Gary Gordon said: “The orphan drug designation is an important regulatory advancement as we further our development in recurrent glioblastoma multiforme, a disease that is uniformly fatal with limited treatment options.

“We are pleased to continue developing ABT-414 in Phase II trials in patients with glioblastoma multiforme based on the results of our Phase I programme.”

AbbVie is currently evaluating the safety and efficacy of ABT-414 in patients with glioblastoma multiforme, the most aggressive type of malignant primary brain tumour.

In May, the company presented results from the Phase I clinical trial evaluating ABT-414 in combination with temozolomide in patients with recurrent or unresectable glioblastoma multiforme.

The Phase I trial was designed to assess the toxicities, pharmacokinetics and recommended Phase II dose of ABT-414 when administered every other week in combination with temozolomide.

Other important assessments included adverse events, pharmacokinetic parameters, objective response and tumour tissue epidermal growth factor receptor biomarkers.

The study results showed four objective responses, including one complete response.

AbbVie has developed ABT-414 with components in-licenced from Life Science Pharmaceuticals and Seattle Genetics.

ABT-414 is also being evaluated in clinical trials for the treatment of patients with squamous cell tumours.

About ABT-414
ABT-414 is an anti-EGFR (epidermal growth factor receptor) monoclonal antibody drug conjugate (ADC). As an ADC, ABT-414 is designed to be stable in the bloodstream and only release the potent cytotoxic agent once inside targeted cancer cells. Developed by AbbVie researchers with components in-licensed from Life Science Pharmaceuticals, ABT-414 is currently being investigated for the treatment of glioblastoma multiforme, the most common and most aggressive malignant primary brain tumor. ABT-414 is also in clinical trials for the treatment of patients with squamous cell tumors. ABT-414 is an investigational compound and its efficacy and safety have not been established by the FDA.

About Glioblastoma Multiforme
Glioblastoma is the most common and most aggressive type of malignant primary brain tumor. Each year in the U.S. and Europe, two to three out of every 100,000 people are diagnosed with glioblastoma, which has a five year survival rate of less than 3 percent. Prior to diagnosis, most patients experience a serious symptom of glioblastoma, such as a seizure. Typically patients succumb to the disease approximately 15 months after diagnosis. Treatment for glioblastoma remains challenging and no long-term treatments are currently available. Standard treatment is surgical resection, radiotherapy and concomitant adjunctive chemotherapy. More than 8,700 patients are enrolled in industry-sponsored clinical studies.

ref………

A phase 1 study evaluating ABT-414 in combination with temozolomide (TMZ) for subjects with recurrent or unresectable glioblastoma (GBM)
50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2021

ABT-414: An anti-EGFR antibody drug conjugate for the treatment of glioblastoma patients
18th Annu Sci Meet Soc Neuro-Oncol (November 21-24, San Francisco) 2013, Abst ET-079

ABT-414: An anti-EGFR antibody-drug conjugate as a potential therapeutic for the treatment of patients with squamous cell tumors
25th EORTC-NCI-AACR Symp Mol Targets Cancer Ther (October 19-23, Boston) 2013, Abst A250

A Phase I/II Study Evaluating the Safety, Pharmacokinetics and Efficacy of ABT-414 in Subjects With Advanced Solid Tumors Likely to Over-Express the Epidermal Growth Factor Receptor (EGFR) (NCT01741727)
ClinicalTrials.gov Web Site 2012, December 07

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FDA grants breakthrough therapy designation to Boehringer’s Idarucizumab, BI 655075


  • 1-​225-​Immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus γ1-​chain) (225→219′)​-​disulfide with immunoglobulin G1, anti-​(dabigatran) (human-​Mus musculus κ-​chain)Protein SequenceSequence Length: 444, 225, 219

BI 655075, Idarucizumab

  • Idarucizumab [INN]
  • UNII-97RWB5S1U6

 CAS 1362509-93-0

Treatment of dabigatran associated haemorrhage

 

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for Boehringer Ingelheim Pharmaceuticals’ idarucizumab, an investigational fully humanised antibody fragment being studied as a specific antidote for Pradaxa.
Boehringer Ingelheim Pharmaceuticals Medicine & Regulatory Affairs senior vice-president Sabine Luik said: “We are committed to innovative research and to advancing care in patients taking Pradaxa.

http://www.pharmaceutical-technology.com/news/newsfda-grants-breakthrough-therapy-designation-boehringers-idarucizumab-4304367

http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2013-004813-41-EE

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-001438-PIP01-13/pip_001159.jsp&mid=WC0b01ac058001d129

  1. IDARUCIZUMAB (BI 655075)
    • What is it?  It is a humanized antibody fragment directed against dabigatran; generated from mouse monoclonal antibody against dabigatran; humanized and reduced to a FAb fragment.
    • What anticoagulant drugs might it reverse?  Dabigatran.
    • Clinical trial status:  (a) A phase 3 study of patients on dabigatran with major bleeding or needing emergency surgery is in the planning stages and will likely start in 2014. (b) A phase 1 study to determine the effect of idarucizumab on coagulation tests in dabigatran-treated healthy volunteers has been completed (NCT01688830), another two are ongoing (NCT01955720; NCT02028780).

Pradaxa Antidote, Idarucizumab Designated Breakthrough Therapy

Boehringer Ingelheim announced that the FDA has granted Breakthrough Therapy designation to idarucizumab, an investigational fully humanized antibody fragment (Fab), being evaluated as a specific antidote for Pradaxa (dabigatran etexilate mesylate).

Data from a Phase 1 trial demonstrated that idarucizumab was able to achieve immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy humans. The on-set of action of the antidote was detected immediately following a 5-minute infusion while thrombin time was reversed with idarucizumab. Reversal of the anticoagulation effect was complete and sustained in 7 of 9 subjects who received the 2g dose and in 8 out of 8 subjects who received the 4g dose. The 1g dose resulted in complete reversal of anticoagulation effect; however, after approximately 30 minutes there was some return of the anticoagulation effects of dabigatran.

RELATED: Anticoagulant Dosing Conversions

A global Phase 3 study, RE-VERSE AD, is underway in patients taking Pradaxa who have uncontrolled bleeding or require emergency surgery or procedures. Currently there are no specific antidotes for newer oral anticoagulants.

Pradaxa is approved to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation (AF). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with parenteral anticoagulant for 5–10 days. To reduce risk of recurrent DVT/PE in patients who have been previously treated.

For more information call (800) 542-6257 or visit Boehringer-Ingelheim.com.

P/0069/2014: European Medicines Agency decision of 17 March 2014 on the agreement of apaediatric investigation plan and on the granting of a deferral for idarucizumab (EMEA-001438-PIP01-13)

 

 

Sanofi gives back rights to Merrimack cancer drug


Sanofi gives back rights to Merrimack cancer drug

After a series of late-stage failures, Sanofi has returned the rights to the cancer compound MM-121 to Merrimack Pharmaceuticals.

MM-121, a monoclonal antibody designed to block ErbB3 activation in patients with heregulin-positive tumours, has been tested in Phase II trials in partnership with the French giant in ovarian, breast and lung cancer. However, none of them have met their primary endpoints and Sanofi has decided  to pull the plug, although it will continue to fund the existing MM-121 Phase II programme for the next six months.

SAR256212 (MM-121)


SAR256212 (MM-121) HER3 ErbB3 antibody

SAR256212 (MM-121) HER3 ErbB3 antibody

Targeting ErbB3

ErbB3 is a kinase-dead critical mediator of pro-survival signaling through PI3K/AKT activation and potentially through activation of other pathways involved in proliferation, differentiation, and survival of cancer cells.20 Signaling is mediated by ErbB3 ligands such as heregulin (HRG) and epidermal growth factor receptor (EGFR) ligands like betacellulin (BTC).21 Signaling through ErbB3 is a major mechanism by which cancer cells acquire resistance to targeted therapies (including EGFR and HER2 inhibitors); chemotherapies; and, potentially, radiotherapy.20,21References:
20. Schoeberl et al. Cancer Res. 2010;70:2485-2494; 21. Schoeberlet al. Sci Signal. 2009;2:ra31;  

Investigational anti-ErbB3 mAB

SAR256212 is an investigational fully human monoclonal antibody that targets the HER3 (ErbB3) receptor.21 SAR256212 potently inhibits ligand-induced signaling through HER3.21 By targeting ErbB3, SAR256212 blocks heregulin (HRG1-β1) binding to HER3, induces HER3 internaliztion and degradation, and blocks BTC-induced phosphorylation of HER3, leading to inhibition of HRG1-β1- and BTC-induced survival signaling.20 SAR256212 activity has been evaluated in a broad range of preclinical tumor xenograft models.21

The clinical significance of these findings is currently under investigation.

SAR256212 | Sanofi Oncology Pipeline

SAR256212 (MM-121). SAR256212 (MM-121) HER3 ErbB3 antibody. Targeting ErbB3. ErbB3 is a kinase-dead critical mediator of pro-survival signaling …

VIDEO...http://www.sanofioncology.com/pipeline/SAR256212.aspx

 

Clinical development

SAR256212 is being codeveloped with Merrimack Pharmaceuticals Inc. SAR256212 is currently being investigated in a phase I trial in patients with refractory advanced solid tumors; in a phase I/II trial, in combination with erlotinib, in patients with NSCLC; in a phase I trial in combination with the investigational agent SAR245408 in solid tumors; in a phase I trial in combination with cetuximab and irinotecan in solid tumors; and in a phase I trial in combination with multiple chemotherapeutic agents in solid tumors. SAR256212 is also being investigated in a phase II trial in ER/PR+ HER2- breast cancer patients in combination with exemestane. In combination with paclitaxel, SAR256212 is being studied in a phase II trial in ER/PR+ HER2- breast cancer and TNBC, and a phase II trial in platinum-resistant/refractory ovarian cancer.

ER=estrogen receptor; HER2=human epidermal growth factor receptor 2; PR=progesterone receptor; TNBC=triple negative breast cancer.

SAR256212 is an investigational agent and has not been approved by the FDA or any other regulatory agency worldwide for the uses under investigation

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
Cancer Res. 2010 Mar 15;70(6):2485-94. doi: 10.1158/0008-5472.CAN-09-3145. Epub 2010 Mar 9.

An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation.

Author information

  • 1Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.

BI-836845 a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.


BI-836845

Human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2

IGF pathway modulator (iv, cancer),  Boehringer Ingelheim;

Phase 2 Clinical

Anticancer protein kinase inhibitor; Anticancer monoclonal antibody

WO-2008155387

Boehringer Ingelheim International Gmbh

Boehringer Ingelheim is developing BI-836845, a fully human mAb targeting IGF-1 created using HuCAL technology from Morphosys, for the potential iv infusion treatment of cancer, including solid tumors and breast cancer.

In April 2011, a phase I trial was initiated in the UK . In October 2011, another phase I trial was initiated in Taiwan. In February 2014, recruitment was ongoing. At that time, the trial was expected to be completed in March 2015 In June 2014, the drug was listed as being in phase I development for solid tumors in Japan and for breast cancer

In May 2014, an open-label, randomized, parallel-assigned, phase II trial (NCT02123823; 1280.4; 2013-001110-15) to evaluate the safety and efficacy of BI-836845 and everolimus in combination with exemestane in women with breast cancer (expected n = 198) was planned to be initiated in Belgium, France and the Netherlands. At that time, the trial was expected to complete in December 2017

In June 2014, an open-label, single-group assigned, phase I trial (NCT02145741; 1280.15) to evaluate BI-836845 in Japanese patients (expected n = 18) with advanced solid tumors was planned to be initiated in Japan. At that time, the trial was expected to complete in June 2015
In March 2011, a non-randomized, open-label, phase I study (NCT01317420; 1280.2; 2010-021714-29) was planned to begin later that month in patients with solid tumors (expected n = 70) in the UK, to assess the safety, efficacy, pharmacokinetics, pharmacodynamics and pharmacogenomics of BI-836845. The study began in April 2011; at that time, completion was expected in March 2013 .

In June 2012, preclinical data were presented at the 48th ASCO meeting in Chicago, IL. In the study, the combination of BI-836845 plus rapamycin was more effective than single agent therapy at inhibiting Ewing’s sarcoma cell proliferation in vitro and in a nude mouse xenograft model .

In November 2011, preclinical data were presented at the 23rd AACR-NCI-EORTC International Conference in San Francisco, CA. BI-836845 potently inhibited proliferation of the multiple myeloma cell line LP-1 with an EC50 of 0.4 nM.

BI-836845 is a human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2 (insulin growth factor-2). Phase II clinical trials are ongoing at Boehringer Ingelheim for the treatment of patients with breast cancer, and phase I clinical trials are ongoing with patients with advanced solid tumors.

Insulin-like growth factor-1 (IGF-1; a 70 amino-acid polypeptide) and insulin-like growth factor-2 (IGF-2; a 67 amino-acid polypeptide) are 7.5-kD soluble factors present in serum that can potently stimulate the growth of many mammalian cells (reviewed by Pollack et al., 2004). Although IGFs can be detectable in a number of tissues the main source of circulating IGFs is the liver which secretes the IGFs and IGF binding proteins (IGFBPs) in response to a complex signaling pathway that is initiated in the pituitary gland and transduced via growth hormone. On secretion into the bloodstream the IGFs form complexes with the IGFBPs which not only protects them from proteolytic degradation in the serum en route to their target tissues but also prevents their association with the IGF receptors. In addition to this endocrine source of IGFs they are also known to be secreted in an autocrine or paracrine manner in target tissues themselves. This is known to occur during normal fetal development where the IGFs play a key role in the growth of tissues, bone and organs. It is also seen in many cancer tissues where there is thought to be paracrine signaling between tumour cells and stromal cells or autocrine IGF production by the tumour cells themselves (reviewed by LeRoith D, 2003).

30 May 2014

MEDIA ALERT

ASCO 2014: Boehringer Ingelheim to present latest oncology research, including overall survival results

• Highly anticipated new overall survival data for Giotrif® (afatinib*) to be presented on June 2nd (3:00 – 6:00 PM, E Hall D2 [Abstract #8004 scheduled for 4:00 – 4:12 PM])
• 7 total abstracts accepted for Giotrif® (afatinib*), nintedanib** and BI 836845**: 1 for oral presentation and 6 posters

BI 836845 (IGF ligand antibody)**
A Phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers Chia-Chi Lin, Kwang-Yu Chang, Dennis Chin-Lun Huang, Vicky Marriott, Ludy van Beijsterveldt, Li-Tzong Chen, Ann-Lii Cheng Sunday, June 1
8:00 – 11:45 AM
S Hall A2
(Abstract #2617
Poster #80)
Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumours Rihawi K, Ong M, Michalarea V, Bent L, Buschke S4, Bogenrieder T, Anthoney A, de Bono J, Twelves CJ Sunday, June 1
8:00 – 11:45 AM
S Hall A2
(Abstract #2622
Poster #85)

 

 

 

The activity of the IGFs is thought to be regulated by a complex and relatively poorly understood interaction involving seven different IGFBPs and other serum proteins. Activation of the IGFs involves their release from this ternary complex after proteolytic release of the serum binding protein and IGFBPs, this is thought to occur in close proximity to cell surfaces where the IGFs are then free to bind to their receptors and transduce intracellular signals that ultimately leads to cellular proliferation and the inhibition of apoptosis. IGF-1 and IGF-2 are able to bind to the IGF-1 receptor (IGF-1R) expressed on many normal tissues, which functionally is a 460 kD heterotetramer consisting of a dimerised alpha- and beta-subunit, with similar affinities (Rubin et al., 1995). IGF-2 can also bind to the IGF-2 receptor (also know as the mannose-6-phosphate receptor) which does not have any known signaling function, rather it is thought to act as a sink for IGF-2 and prevent it from binding and signaling through the IGF-1R. In this respect the IGF-2R has been demonstrated to be a tumour suppressor protein. The IGF-1R is structurally similar to the insulin receptor which exists in two forms, IR-A and IR-B, which differ by an alternatively spliced 12 amino acid exon deletion in the extracellular domain of IR-A. IR-B is the predominant IR isoform expressed in most normal adult tissues where it acts to mediate the effects of insulin on metabolism. IR-A on the other hand is known to be highly expressed in developing fetal tissues but not in adult normal tissues. Recent studies have also shown that IR-A, but not IR-B, is highly expressed in some cancers. The exon deletion in IR-A has no impact on insulin binding but does cause a small conformational change that allows IGF-2 to bind with much higher affinity than for IR-B (Frasca et al., 1999; Pandini et al., 2002). Thus, because of it’s expression in cancer tissues and increase propensity for IGF-2 binding, IR-A may be as important as IGF1-R in mediating the mitogenic effects of IGF-2 in cancer.

Binding of the IGFs to IGF-1R triggers a complex intracellular signaling cascade which results in activation of proteins that stimulate growth and inhibit apoptosis (reviewed by Pollack et al., 2004). In terms of growth, upregulated translation is induced by the activation of p70 S6 kinase, which in turn phosphorylates the S6 ribosomal protein (Dufner and Thomas, 1999). Thus, IGF-stimulated cell growth can be measured by the rapid increase in phosphorylated S6 ribosomal protein.

Unlike the EGFR and Her2neu receptors there is no known amplification of the IGF1-R or IR-A receptors in cancers indicating that receptor activation is controlled by the presence of active ligand. There is a very large body of scientific, epidemiological and clinical literature implicating a role for the IGFs in the development, progression and metastasis of many different cancer types (reviewed by Jerome et al., 2003; and Pollack et al., 2004).

For example, in colorectal cancer the expression of IGF-2 mRNA and protein is elevated in clinical colorectal tumour specimens compared with adjacent normal tissue (Freier et al., 1999; Li et al., 2004). There is also a positive correlation of elevated IGF serum levels with proliferating cell index in patients with colorectal neoplasia (Zhao et al., 2005). In addition, elevated circulating levels of IGF-2 correlate with an increased risk of developing colorectal cancers and adenomas (Renehan et al., 2000a) and b); Hassan et al., 2000). Loss of parental imprinting (LOI) of the IGF-2 gene, an epigenetic alteration that results in elevated IGF-2 expression, is a heritable molecular trait that has recently been identified in patients with colorectal and other tumour types. Loss of IGF-2 imprinting has been shown to be associated with a five-fold risk of colorectal neoplasia (Cui et al., 2003; Cruz-Correa et al., 2004) and adenomas (Woodson et al., 2004). Antibodies targeting the alpha-subunit of the IGF-1R which block IGF binding and internalize the receptor have been shown to delay the growth of the xenografted colon cancer-derived cell lines such as COLO 205 (Burtrum et al., 2003).

Elevated levels of IGFs are associated with a poor prognosis in human pulmonary adenocarcinomas (Takanami et al., 1996) and IGFs are expressed and secreted by many SCLC— and NSCLC-derived cell lines (Quinn et al., 1996). Transgenic over-expression of IGF-2 induces spontaneous lung tumours in a murine model (Moorhead et al., 2003). In terms of hepatocellular carcinoma (HCC), human clinical specimens and animal models of HCC express higher levels of IGF mRNA and protein than corresponding normal tissues and this has been correlated with increased tumour growth (Wang et al., 2003; Ng et al., 1998). IGF-2 has also been shown to be a serological marker of HCC with elevated levels in the serum of HCC patients compared with controls (Tsai et al., 2005). An orthotopic xenograft tumour model of HCC was established using Hep 3B cells, and used to demonstrate that inhibition of IGF-2 expression using a methylated oligonucleotide enhances survival (Yao et al., 2003a) and b).

Many childhood solid tumours such as Ewing sarcoma and rhabdomyosarcoma appear to be particularly dependent on the IGF signaling pathway for their growth (Scotlandi et al., 1996). LOI of the IGF-2 gene has been implicated as a primary genetic event in the development for embryonal rhabdomyosarcoma (Fukuzawa et al., 1999). Autocrine IGF signaling is also thought to strongly influence the growth of Ewing sarcoma in cases where the type-1 EWS-FLI1 chimeric transcription factor is expressed through a chromosomal translocation resulting in elevated expression of target genes including the IGF ligands and IGF-1R, and reduced expression of IGFBP-3. Antibodies and small molecule compounds targeting the IGF-1R have been shown to reduce the growth of xenografted pediatric solid tumour derived cell lines (Kolb et al., 2008; Manara et al., 2007).

Using IGF ligand-specific antibodies it has been demonstrated that the growth of human prostate cancer cells in adult human bone implanted into SCID mice can be inhibited (Goya et al., 2004). In addition, it was demonstrated that the same IGF ligand antibodies could block the paracrine supply of IGF and suppress the liver metastasis of human colorectal cancer cells in a murine xenograft system (Miyamoto et al., 2005).

There is also considerable evidence suggesting that the IGF signaling system reduces the sensitivity of cancers to chemotherapeutic agents and radiation. One of the earliest findings in this respect was the demonstration that IGF-1R knock-out mouse embryos are refractory to transformation by viruses, oncogenes and over-expressed growth factor receptors (Sell et al., 1993; Sell et al., 1994) and that over-expression of IGF-1R protects cells from UV irradiation and gamma radiation-induced apoptosis (Kulik et al., 1997). Furthermore, using liver tumour cell lines that secrete large amounts of IGF-2, it was found that neutralization of IGF-2 significantly increased response to chemotherapeutic agents such as cisplatin and etoposide in vitro, especially at lower, cytostatic doses, suggesting that IGF-2 can reduce the susceptibility to chemotherapeutic agents (Lund et al., 2004). Consistent with these findings it has been demonstrated that antibodies targeting the IGF-1R increase the susceptibility of tumour xenografts to growth inhibition by chemotherapeutic drugs and radiation (Goetsch et al., 2005).

A number of antibodies that show cross-reactive binding to human IGF-1 and human IGF-2 have been reported. Antibody sm1. was raised against human IGF-1 and shows 40% cross-reactivity to human IGF-2 and was shown to inhibit the proliferation of a mouse fibroblast cell line BALB/c3T3 which was stimulated with 20 ng/ml human IGF-1 (Russell et al., 1984). In a study designed to functionally epitope map IGF-1 by raising monoclonal antibodies to whole IGF-1 protein and portions of the protein a number of antibodies where identified that cross reacted with IGF-2 (Manes et al., 1997). The percent cross-reactivity with IGF-2 ranged from 0 to 800% and several antibodies were identified which were equally IGF-1 and IGF-2 reactive. KM1486 is a rat monoclonal antibody that cross-reacts with human IGF-1 and IGF-2 and it was demonstrated that KM1486 can inhibit growth of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice (Goya et al., 2004). In addition, it was demonstrated that KM1486 suppresses the liver metastasis of human colorectal cancers (Miyamoto et al., 2005). KM1486 has also been described in WO 03/093317, JP 2003-310275, WO 2005/018671, WO 2005/028515, and WO 2005/027970.

For the treatment of human disease an antibody with a fully human sequence is highly desirable in order to minimize the risk of generating a human anti-antibody reaction and neutralizing antibodies that will rapidly eliminate the administered antibody from the body and thereby reduce the therapeutic effect. As such, and given the roles of IGF-1 and IGF-2 dependent signaling in the development and progression of cancers it would be desirable to obtain high affinity fully human antibodies that co-neutralise the mitogenic effects of both ligands.

In addition, to maximize the therapeutic potential of such an antibody, it is important to have a suitably long terminal half life (T1/2). Prior to terminal half life determination in human subjects, the most accurate estimation of an antibody’s human terminal half life can be obtained from administration to non-human primates such as cynomolgus monkeys. For example, bevacizumab, a registered humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used for the treatment of several human cancers, has a terminal half-life in cynomolgus monkeys of 8.57±0.38 days (Lin et al., 1999), which translates to a terminal half life in humans of approximately 20 days allowing for a single administration once every two weeks (Lu et al., 2008).

 

It was a further object of the invention to obtain an antibody that does not affect binding of insulin to its receptor.

The clinical development of therapeutic agents is supported by pharmacodynamic biomarkers of drug activity. Clinical studies with antibodies targeting the IGF-1R have demonstrated that an increase in total serum IGF-1 levels may be a useful pharmacodynamic marker for these agents (Pollack et al., 2007). The reason for the increase in total serum IGF-1 levels is likely due to a feedback mechanism involving pituitary growth hormone (GH) secretion which releases both IGF-1 and IGFBPs from the liver. Indeed, in humans it has been demonstrated that free or bioactive IGF-1, which represents only around 1% of total IGF-1 levels, determines the feedback response (Chen et al., 2005). The inventors thus sought to confirm whether total serum IGF-1 levels are also a useful pharmacodynamic marker for the activity of a therapeutic anti-IGF antibody. In this case it would be desirable for such antibody to be cross-reactive with IGFs from a suitable animal species, e.g. mouse or rat, such that a pharmacodynamic effect can already be tested pre-clinically.

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.

 

Production of MAb

Fig.1 Production of MAb

 

 

Adam, P.J.; Friedbichler, K.; Hofmann, M.H.; Bogenrieder, T.; Borges, E.; Adolf, G.R.
BI 836845, a fully human IGF ligand neutralizing antibody, to improve the efficacy of rapamycin by blocking rapamycin-induced AKT activation
48th Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2012, Abst 3092

 

Lin, C.-C.; Chang, K.-Y.; Huang, D.C.; Marriott, V.; Van Beijsterveldt, L.; Chen, L.-T.; Cheng, A.-L.
A phase I dose escalation study of weekly BI 836845, a fully human, affinity-optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid cancers
50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2617

 

Adam, P.J.; Ostermann, E.; Lamche, H.R.; Hofmann, M.H.; Kroez, M.; Borges, E.; Adolf, G.R.
Pharmacodynamic properties and anti-tumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody
AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (November 12-16, San Francisco) 2011, Abst A208

 

Rihawi, K.; Ong, M.; Michalarea, V.; et al.
Phase I dose escalation study of 3-weekly BI 836845, a fully human, affinity optimized, insulin-like growth factor (IGF) ligand neutralizing antibody, in patients with advanced solid tumors
50th Annu Meet Am Soc Clin Oncol (ASCO) (May 30-June 3, Chicago) 2014, Abst 2622

Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland


 

Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland

 

Glenmark opens a new cGMP-compliant monoclonal antibody manufacturing facility in La Chaux-de-Fonds, Switzerland

• State of the art manufacturing facility for supply of clinical trial material
• With the facility Glenmark has end-to-end capabilities for the development of novel, state-of-the-art monoclonal antibodies including bi-specific antibodies
La Chaux-de-Fonds, Switzerland, June 4, 2014 – Glenmark Pharmaceuticals S.A (GPSA), a wholly owned subsidiary of Glenmark Pharmaceuticals Limited, India (GPL), announced the opening of its new cGMP compliant monoclonal antibody manufacturing facility in La Chaux-de-Fonds, Switzerland. This manufacturing facility supplements Glenmark’s existing in-house discovery and development capabilities and will supply material for clinical development.

The manufacturing facility has been designed for use of single use bioreactor systems and also houses a suite for manufacturing cell banks. The facility is fully compliant with quality, environmental and safety standards for manufacturing clinical trial material.

http://www.moneycontrol.com/stocks/stock_market/corp_notices.php?autono=813829

 http://www.finalaya.com/685643_ann/Glenmark_Pharmaceuticals_inaugurates_new_Antibody_Manufacturing_Facility_in_La_ChauxdeFonds_Switz_.aspx?S=&FD=&TD=&CT=&YR=&MON=&CMP=

4th-Jun-2014 10:33Source: BSE

Glenmark – Glenmark Pharmaceuticals inaugurates new Antibody Manufacturing Facility in La Chaux-de-Fonds, Switzerland 

The company says the facility supplements existing in-house discovery and development capabilities and will supply material for clinical development. Glenmark Pharmaceuticals’ Swiss research centre is an integrated antibody discovery and development unit with in-house capabilities and infrastructure for conducting antibody discovery, cell line development, in vitro testing and characterisation of antibodies, process development and analytical research. The new manufacturing facility supplements the research and development capabilities and will enable production of clinical grade material.

Single-use bioreactor systems and a suite for manufacturing cell banks are included in the new facility, which is fully compliant with quality, environmental and safety standards for manufacturing clinical trial material. Michael Buschle, President – Biologics, at Glenmark Pharmaceuticals, said: ‘This state-of-the-art manufacturing facility is a testimony to Glenmark’s commitment to growing its R&D and manufacturing facility in the canton of Neuchâtel.

We have been doing cutting-edge work in the area of novel monoclonal antibodies and have several monoclonal antibody candidates and bispecific antibodies in the pipeline.

The manufacturing facility will help us bring these antibodies to the clinic faster.’ There are currently 69 staff at the research centre developing biologics for the treatment of pain, inflammatory, oncologic and respiratory conditions. In 10 years, the centre has filed several patents on novel biologic entities: GBR 500, its most advanced candidate, has been licensed to Sanofi and is currently in Phase II development; GBR 900, a molecule for the treatment of chronic pain, is currently in Phase I; and GBR 830, an anti OX-40 antagonist, is scheduled to enter the clinic later this year

La Chaux-de-Fonds, Switzerland ………city

EU approves Takeda’s bowel drug Entyvio


EU approves Takeda's bowel drug Entyvio

Hot on the heels of an approval in the US, regulators in Europe have now also given Takeda’s Entyvio (vedolizumab) the nod for two inflammatory bowel diseases. The European Commission has granted Marketing Authorisation for use of the gut-selective humanised monoclonal antibody to treat adults with moderately to severely active ulcerative colitis (UC) and adults with moderately to severely active Crohn’s disease (CD).

Read more at: http://www.pharmatimes.com/Article/14-05-27/EU_approves_Takeda_s_bowel_drug_Entyvio.aspx#ixzz334DL7xQJ

Amgen-AstraZeneca Psoriasis Drug Brodalumab (AMG 827) Hits Phase 3 Endpoints


 

 

AstraZeneca and Amgen announced that the Phase 3 AMAGINE-1TM study evaluating brodalumab in patients with moderate-to-severe plaque psoriasis met all primary and secondary endpoints for both evaluated doses.

Read more… http://www.dddmag.com/news/2014/05/amgen-astrazeneca-psoriasis-drug-hits-phase-3-endpoints?et_cid=3935059&et_rid=523035093&type=cta

Brodalumab is a human monoclonal antibody designed for the treatment of inflammatory diseases.[1] It is being tested for the treatment of moderate to severe psoriasis[2] in Phase III clinical trials as of November 2013.[3][4]

Brodalumab was developed by Amgen, Inc.

Mechanism of action

Brodalumab binds to the interleukin-17 receptor and so prevents interleukin 17 (IL-17) from activating the receptor. This mechanism is similar to that of another anti-psoriasis antibody, ixekizumab, which however binds to IL-17 itself.[2]
At present, brodalumab is the only experimental drug in development that inhibits the IL-17 receptor, thus inhibiting several of the IL-17 ligands at once from transmitting signals to the body. Other agents currently in development seek to target the individual IL-17 ligands. By inhibiting the attachment of these ligands with the receptor, brodalumab stops the body from receiving signals that may otherwise cause inflammation and other ailments.

Researchers are currently investigating brodalumab for the treatment of psoriasis (Phase II and planned Phase III), asthma (Phase II), and psoriatic arthritis (Phase II).

Psoriasis is a chronic disease of the immune system that causes the skin cells to grow at a faster rate. Worldwide, the condition affects around 125 million individuals. Even though several types of psoriasis exist, around 80% of sufferers have plaque psoriasis. Plaque psoriasis can cause painful and itchy red, scaly patches to appear on the skin.

Brodalumab

(AMG 827)

Monoclonal antibody
Type Whole antibody
Source Human
Target Interleukin 17 receptor A
Clinical data
Legal status Investigational
Identifiers
CAS number 1174395-19-7
ATC code None
KEGG D10061 
Chemical data
Formula C6372H9840N1712O1988S52 
Mol. mass 144.06 kDa

 

About Brodalumab (AMG 827)

Brodalumab is a novel human monoclonal antibody that binds to the interleukin-17 (IL-17) receptor and inhibits inflammatory signaling by blocking the binding of several IL-17 ligands to the receptor. By stopping IL-17 ligands from activating the receptor, brodalumab prevents the body from receiving signals that may lead to inflammation. The IL-17 pathway plays a central role in inducing and promoting inflammatory disease processes. In addition to moderate-to-severe plaque psoriasis (Phase 3), brodalumab is currently being investigated for the treatment of psoriatic arthritis (Phase 3) and asthma (Phase 2).

About the Amgen and AstraZeneca Collaboration

In April 2012, Amgen and AstraZeneca formed a collaboration to jointly develop and commercialize five monoclonal antibodies from Amgen’s clinical inflammation portfolio. With oversight from joint governing bodies, Amgen leads clinical development and commercialization for brodalumab (Phase 3 for moderate-to-severe plaque psoriasis and psoriatic arthritis, Phase 2 for asthma) and AMG 557/MEDI5872 (Phase 1b for autoimmune diseases such as systemic lupus erythematosus). AstraZeneca, through its biologics arm MedImmune, leads clinical development and commercialization for MEDI7183/AMG 181 (Phase 2 for ulcerative colitis and Crohn’s disease), MEDI2070/AMG 139 (Phase 2 for Crohn’s disease) and MEDI9929/AMG 157 (Phase 2 for asthma).

About Amgen

Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics. This approach begins by using tools like advanced human genetics to unravel the complexities of disease and understand the fundamentals of human biology.

Amgen focuses on areas of high unmet medical need and leverages its biologics manufacturing expertise to strive for solutions that improve health outcomes and dramatically improve people’s lives. A biotechnology pioneer since 1980, Amgen has grown to be the world’s largest independent biotechnology company, has reached millions of patients around the world and is developing a pipeline of medicines with breakaway potential.

For more information, visit www.amgen.com and follow us on www.twitter.com/amgen.

 

About AstraZeneca

AstraZeneca is a global, innovation-driven biopharmaceutical business that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of cardiovascular, metabolic, respiratory, inflammation, autoimmune, oncology, infection and neuroscience diseases. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information please visit: www.astrazeneca.com.

References

  1. “Statement On A Nonproprietary Name Adopted By The USAN Council: Brodalumab”. American Medical Association.
  2. “Neue Antikörper in der Pipeline”. Pharmazeutische Zeitung (in German) (12). 2012.
  3. ClinicalTrials.gov NCT01708590 Study of Efficacy, Safety, and Withdrawal and Retreatment With Brodalumab in Moderate to Severe Plaque Psoriasis Subjects (AMAGINE-1)
  4. ClinicalTrials.gov NCT01708629 Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects (AMAGINE-3)

http://ksclinic.exblog.jp/18270693/

学術面で最初の講演は、米国のJames Krueger教授による「Th1細胞,Th17細胞,Th22細胞が複雑なサイトカインネットワークによって、細胞レベル、分子レベルで乾癬を引き起こす」でした。その要約を示すスライドを幾枚か失敬します(Krueger先生、ごめんなさい)。

乾 癬の原因究明、病態(病気の起こり方)解明の主役となった免疫学的研究の最先端を行くKrueger先生の、最新情報がコンパクトにまとまった素晴らしい 講演でした。生物学的製剤の治療根拠となるサイトカインネットワークは、現在TipDC – Th17経路によって、きわめて明快に説明されるようになり、Th17細胞が放出するIL17が表皮細胞(ケラチノサイト)の乾癬化を起こします。現在使 用されている抗TNFα製剤、抗IL12/23製剤が、より上流(免疫反応の根っこ)で免疫反応を抑制するのに比べ、IL17はより末梢における乾癬の原 因サイトカインであることから、IL17の抑制は、より乾癬をピンポイントで、そして副作用もミニマムにすることが期待される。

現在、3種類のIL17抑制薬剤が開発され、治療研究が進められている。
①IL17A抗体(Secukinumab Novartis社)
②IL17A抗体(Ixekizumab Lilly社)
③IL17A受容体抗体(Brodalumab Amgen社)


その一つ、Secukinumabの効果(PASI75)=すごく乾癬がよくなる)では、たった3回の注射で90%以上の患者がPASI75を達成する。


PASI90(=乾癬がほとんどなくなる)でみても、60%の患者で達成されている。

Secukinumabの臨床効果。上の段は「プラセボ(偽薬)」、下の段がSecukinumab。

Ixekizumabの効果(PASI90)。約80%の患者で達成されている。驚異的である。

Brodalumabの臨床効果

印象深かった講演をもう一つ、詳細に紹介いたします。
米 国のAnne Bowcock教授の”The genetics of psoriasis: Old risks, novel loci (乾癬の遺伝子研究:昔から言われていた異常、新しく見つかった場所)です。Bowcock教授は、乾癬の原因遺伝子について世界で最初に報告した研究者 です。ここでも少し講演スライドを拝借(Bowcock先生、ごめんなさい)。

Bowcock 教授は1999年、乾癬家系の詳細な遺伝子調査から第17染色体に乾癬と関わり深い遺伝子異常があることをみつけ、科学雑誌Scienceに報告した。 21世紀を迎える直前のことであり、遠からず乾癬の原因遺伝子が確定し、完治治療を開発することも夢ではないと、当時期待したものでした。
ところが、次々と関連遺伝子はみつけられるものの(現在は30種類以上)、肝心の原因遺伝子、特定のタンパク、メカニズムは不明のままでした。

Bowcock 教授の息の長い研究は、第17染色体上にあるCARD14と呼ばれるタンパクの、その異常が直接乾癬を起こすことを説き明かしました。CARD14は細胞 膜上にあるタンパクで、細胞外で起こる炎症から生じる様々な刺激物質を、細胞の膜から細胞の中へ伝える役割を果たしています。その伝達経路はNFκBを介 しています(乾癬ではこの経路が活発に動いていることが、高知大学の佐野教授により解明されました)。

遺伝性膿疱性乾癬患者では、このCARD14遺伝子に点突然変異が起こっていることを発見しました。この点突然変異だけで、特殊タイプではありますが、乾癬の原因が特定されたのです。

点突然変異だけではなく、CARD14遺伝子に起こりやすい変異も、ほかの遺伝子異常(PSORS1、MHC遺伝子)、あるいは環境変化が加わると乾癬を引き起こすことも証明しました。

大変感銘深い講演でした。
会議の模様、IFPA代表者会議の報告は、また後日掲載いたします(『2012年9月教室抄録』をご覧ください)。
ブログ「PHOTO & ESSAY」もご覧ください。

FDA OKs Ibalizumab, a Sterile Biologic for HIV


FDA OKs Ibalizumab, a Sterile Biologic for HIV

// // // // // // // // // // // // // // // // // // // // //

 

 

WuXi PharmaTech and TaiMed Biologics announced that the FDA has approved the first batch of the ibalizumab drug substance and sterile drug product, manufactured at WuXi’s biologics facilities, for ongoing treatment of patients under investigator-sponsored INDs. Read more…FULL STORY

http://www.dddmag.com/news/2014/05/fda-oks-ibalizumab-sterile-biologic-hiv?et_cid=3921847&et_rid=523035093&type=cta

FDA OKs Ibalizumab, a Sterile Biologic for HIV

// // // // // // // // // // // // // // // // // // // // //

Ibalizumab is a humanized monoclonal antibody and a member of an emerging class of HIV therapies known as viral-entry inhibitors. It is being developed by TaiMed Biologics for the treatment of HIV/AIDS infection.

 

Glenmark Kicks Off Monoclonal Antibody Pain Studies


 

 

Glenmark Pharmaceuticals S.A., a wholly owned Swiss subsidiary of Glenmark Pharmaceuticals Ltd., announced that GBR 900, a novel monoclonal antibody is entering human trials. GBR 900 targets TrkA, a receptor for nerve growth factor (NGF) involved in chronic pain signaling.

In 2010, Glenmark gained an exclusive worldwide license from Lay Line Genomics S.p.A. (Italy) for anti-TrkA antibodies and their entire intellectual property portfolio in the TrkA field. GBR 900 is the optimized anti-TrkA antibody emerging from this exclusive worldwide license.

read all at

http://www.dddmag.com/news/2014/04/glenmark-kicks-monoclonal-antibody-pain-studies

Glenmark Kicks Off Monoclonal Antibody Pain Studies

Glenmark Pharmaceuticals today said its novel monoclonal antibody for potential treatment of chronic pain is entering human trials.

Glenmark Pharmaceuticals today said its novel monoclonal antibody for potential treatment of chronic pain is entering human trials. 

FDA Approves Cyramza, ramucirumab (IMC-1121B) for Stomach Cancer


 

April 21, 2014 — The U.S. Food and Drug Administration today approved Cyramza (ramucirumab) to treat patients with advanced stomach cancer or gastroesophageal junction adenocarcinoma, a form of cancer located in the region where the esophagus joins the stomach.

Stomach cancer forms in the tissues lining the stomach and mostly affects older adults. According to the National Cancer Institute, an estimated 22,220 Americans will be diagnosed with stomach cancer and 10,990 will die from the disease, this year.

Cyramza is an angiogenesis inhibitor that blocks the blood supply to tumors. It is intended for patients whose cancer cannot be surgically removed (unresectable) or has spread (metastatic) after being treated with a fluoropyrimidine- or platinum-containing therapy.

“Although the rates of stomach cancer in the United States have decreased over the past 40 years, patients require new treatment options, particularly when they no longer respond to other therapies,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Cyramza is new treatment option that has demonstrated an ability to extend patients’ lives and slow tumor growth.”

Cyramza’s safety and effectiveness were evaluated in a clinical trial of 355 participants with unresectable or metastatic stomach or gastroesophageal junction cancer. Two-thirds of trial participants received Cyramza while the remaining participants received a placebo. The trial was designed to measure the length of time participants lived before death (overall survival).

Results showed participants treated with Cyramza experienced a median overall survival of 5.2 months compared to 3.8 months in participants receiving placebo. Additionally, participants who took Cyramza experienced a delay in tumor growth (progression-free survival) compared to participants who were given placebo. Results from a second clinical trial that evaluated the efficacy of Cyramza plus paclitaxel (another cancer drug) versus paclitaxel alone also showed an improvement in overall survival.

Common side effects experienced by Cyramza-treated participants during clinical testing include diarrhea and high blood pressure.

The FDA reviewed Cyramza under its priority review program, which provides an expedited review for drugs that have the potential, at the time the application was submitted, to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cyramza was also granted orphan product designation because it is intended to treat a rare disease or condition.

Cyramza is marketed by Indianapolis-based Eli Lilly.

Source: FDA

http://www.drugs.com/newdrugs/fda-approves-cyramza-stomach-cancer-4033.html?utm_source=ddc&utm_medium=email&utm_campaign=Today%27s+news+summary+-+April+21%2C+2014

 

 

old article

Eli Lilly’s third-quarter earnings fell 9 percent compared with last year, when the maker of Cymbalta and Cialis booked a sizeable revenue-sharing payment from a former drug developer partner.

The Indianapolis company beat Wall Street expectations for the quarter and narrowed its earnings forecast for the year.

Lilly also said Wednesday that the U.S. Food and Drug Administration will give its stomach cancer treatment ramucirumab a priority review, which means the drugmaker will learn about its fate inside of eight months rather than a year, which is the norm.

read at

http://www.dddmag.com/news/2013/10/eli-lillys-profit-slides-gets-priority-review

cut paste old article

Eli Lilly and Co. announced that results from the Phase 3 REGARD trial of ramucirumab (IMC-1121B) as a single agent in patients with advanced gastric cancer who have had disease progression after initial chemotherapy were published today in The Lancet. REGARD is the first Phase 3 study with either a single-agent biologic or an anti-angiogenic therapy to show improved overall survival and progression-free survival in advanced gastric cancer patients.

READ ALL AT

http://www.dddmag.com/news/2013/10/ramucirumab-trial-shows-improved-os-gastric-cancer?et_cid=3516952&et_rid=523035093&type=cta

Ramucirumab (IMC-1121B)[1] is a fully human monoclonal antibody (IgG1) being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF inangiogenesis.

Ramucirumab is being tested in several phase III clinical trials for the treatment of metastatic gastric adenocarcinoma,[2] non-small cell lung cancer,[3] among other types of cancer. On September 26, 2013 Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.[4][5]

This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.

  1.  Statement On A Nonproprietary Name Adopted By The USAN Council – RamucirumabAmerican Medical Association.
  2.  ClinicalTrials.gov NCT01170663 A Study of Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW)
  3.  ClinicalTrials.gov NCT01168973 A Study in Second Line Non Small Cell Lung Cancer
  4. ClinicalTrials.gov NCT00703326 Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer
  5.  Fierce Biotech. “In another stinging setback, Eli Lilly’s ramucirumab fails PhIII breast cancer study”. Retrieved 27 September 2013.

 

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