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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Importance Of Preclinical Imaging In Drug Discovery
The process of discovering and bringing a drug to market consists of several stages, beginning with identification and validation of a drug target and continuing through lead identification by high-throughput screening, lead optimization, and profiling in relevant disease models. When a promising compound is found, a decision must be made on whether to take the drug into development. This long and expensive undertaking typically requires nearly $800 million and takes about 12 years before an approved drug is brought to market .
Shortening the drug discovery and development process is critical to managing this cost and can be achieved by improving the characterization of compounds and their effects in early phases of testing. Imaging has the potential to dramatically increase the efficiency of lead candidate selection by providing earlier and more highly predictive data, compared with traditional methods. Imaging is also well suited to facilitating translation between preclinical testing and clinical evaluation of drugs. Imaging methods are also more easily applied than traditional methods in the newer, more realistic models of human disease that are becoming increasingly prevalent, such as models of invasive disease in the tissue of origin as well as transgenic mouse models.
http://www.drugdiscoveryonline.com/doc/importance-of-preclinical-imaging-in-drug-discovery-0001
Breast Cancer Drugs in Late-Stage Development/Recently Approved
The article is 2012-2013 based and reader discretion is sought to ascertian the stage of approval
Afinitor® (everolimus)
https://newdrugapprovals.wordpress.com/2013/04/27/drug-spotlight-afinitor-everolimus-novartis/
Sponsor: Novartis
Method of Action: Mammalian target of rapamycin (mTOR) inhibitor
Indications/Phase of Trial: Hepatocellular carcinoma; human epidermal growth factor receptor 2-positive (HER2+) breast cancer first-line and second-line; lymphoma; nonfunctional carcinoid tumor (Phase III; all new indications)
Approved in July in U.S., EU for advanced hormone-receptor-positive (HR+) and human epidermal growth factor Receptor 2-negative (HER2-) metastatic breast cancer with exemestane in postmenopausal women who have already received certain other medicines for their cancer
Approved earlier for adults with pancreatic neuroendocrine tumors (PNET) that cannot be treated with surgery; adults with advanced renal cell carcinoma (RCC) when certain other medicines have not worked; adults with angiomyolipoma, seen with tuberous sclerosis complex (TSC), when surgery is not required immediately; and adults and children with TSC who have a brain tumor called subependymal giant cell astrocytoma (SEGA) that cannot be removed completely by surgery
Avastin (Bevacizumab; RG435)
Sponsor: Roche/Genentech
Method of Action: Monoclonal antibody; Vascular endothelial growth factor (VEGF) inhibitor
Indications/Phase of Trial: U.S.: Relapsed ovarian cancer, platinum-sensitive (Registration); first-line metastatic breast cancer and first-line metastatic ovarian cancer (both Phase III).
EU: Relapsed platinum-resistance ovarian cancer (Phase III)
Metastatic colorectal cancer, treatment beyond progression (Registration); adjuvant breast cancer, HER2- and HER2+; adjuvant NSCLC; first-line glioblastoma (GBM) multiforme; high-risk carcinoid (all Phase III)
Approved for metastatic colorectal cancer (mCRC) when started with the first or second intravenous 5-FU–based chemotherapy for metastatic cancer; advanced nonsquamous non-small-cell lung cancer (NSCLC) with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease; metastatic RCC (mRCC) with interferon alfa; and GBM in adult patients whose cancer has progressed after prior treatment. Effectiveness based on tumor response, as no data have shown whether Avastin improves disease-related symptoms or survival in people previously treated for GBM
Approval conditionally granted in 2008 and withdrawn November 2011 for HER2- metastatic breast cancer (mBC) with Paclitaxel
Buparlisib (BKM120)
Sponsor: Novartis
Method of Action: Pan-PI3K inhibitor
Indications/Phase of Trial: mBC (Phase III and confirmatory Phase I/II); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- locally advanced or mBC which progressed on or after aromatase inhibitor (AI) treatment (Phase III; BELLE-2 study recruiting as of November 2012); with Fulvestrant, in postmenopausal women with hormone receptor-positive HER2- AI-treated, locally-advanced or mBC who progressed on or after mTOR inhibitor-based treatment (Phase III; BELLE-3 study, recruiting as of October 2012); with Paclitaxel in patients with HER2- inoperable locally advanced or mBC, with or without PI3K pathway activation (Phase III; BELLE-4 study, recruiting as of November); metastatic castration-resistant prostate cancer (CRPC; Phase II; recruiting as of October); recurrent glioblastoma (Phase II; recruiting as of November); recurrent/metastatic head and neck squamous cell carcinoma (Phase II; recruiting as of October); endometrial cancer (Phase I/II); NSCLC (Phase I/II); prostate cancer (Phase I/II); GBM multiforme (Phase I/II); with Fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer (Phase I); previously treated advanced colorectal cancer (Phase I)
Faslodex (Fulvestrant Injection)
Sponsor: AstraZeneca
Method of Action: Estrogen receptor antagonist
Indications/Phase of Trial: First line HR+ mBC (Phase III; FALCON study commenced Oct. 29)
Approved for HR+ mBC in women who have experienced menopause and whose breast cancer has worsened after they were treated with antiestrogen medications
Herceptin (Trastuzumab; RG597)
Sponsor: Roche, in partnership with Halozyme
Method of Action: Humanized monoclonal antibody designed to target and block the function of HER2+
Indications/Phase of Trial: EU: Early HER2+ breast cancer, subcutaneous formulation (Registration)
Approved for early-stage HER2+ breast cancer that has spread into the lymph nodes, and HER2+ breast cancer that has not spread into the lymph nodes and is estrogen receptor/progesterone receptor-negative (ER-/PR-) or have one high-risk feature. High-risk is defined as estrogen receptor/progesterone receptor-positive (ER+/PR+) with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3. Can be used with Adriamycin® (doxorubicin), Cytoxan® (cyclophosphamide), and either Taxol® (paclitaxel) or Taxotere® (docetaxel); or with Taxotere and Paraplatin® (carboplatin); or alone after treatment with multiple other therapies, including an anthracycline (Adriamycin)-based chemotherapy
Also approved alone for the treatment of HER2+ breast cancer in patients who have received one or more chemotherapy courses for metastatic disease; and with paclitaxel for first-line treatment of HER2+ mBC
Iniparib (Tivolza; BSI-201; SAR240550)
Sponsor: Sanofi, through acquisition of original developer BiPar Sciences
Method of Action: Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor
Indications/Phase of Trial: Stage IV squamous NSCLC (Phase III; NME); solid tumors such as sarcoma and breast, uterine, lung, and ovarian cancers (Phase I/II)
Phase III trial in breast cancer failed January 2011 by failing to improve survival and progression-free survival (PFS) in breast cancer patients
Nexavar® (Sorafenib)
https://newdrugapprovals.wordpress.com/2013/07/16/nexavar-sorafenib/
Sponsor: Onyx Pharmaceuticals
Method of Action: Dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases
Indications/Phase of Trial: Liver cancer adjuvant (Phase III; STORM study); kidney cancer adjuvant (Phase III; SORCE/ASSURE study); thyroid cancer monotherapy (Phase III; DECISION study); breast cancer with capecitabine (Phase III; RESILIENCE study)
Approved for hepatocellular carcinoma (HCC) and RCC
Perjeta (Pertuzumab; RG1273)
Sponsor: Roche/Genentech
Method of Action: HER2/neu receptor antagonist
Indications/Phase of Trial: EU: With Herceptin and docetaxel chemotherapy for previously-untreated HER2+ mBC or locally recurrent, inoperable breast cancer in patients who have not received previous treatment or whose disease has returned after treatment in the early-stage setting (Registration)
U.S.: Approved June 2012 for HER2+ mBC with Herceptin (trastuzumab) and docetaxel, in patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease
Switzerland: Approved August 2012 for HER2+ breast cancer with Herceptin (trastuzumab) and docetaxel in patients with advanced or locally recurring breast cancer that has not previously been treated with chemotherapy
Ridaforolimus (MK-8669; AP23573; formerly Deforolimus)
Sponsor: Merck, under exclusive worldwide license agreement with Ariad Pharmaceuticals
Method of Action: Oral inhibitor of mammalian target of rapamycin inhibitor (mTOR)
Indications/Phase of Trial: Maintenance therapy for metastatic soft-tissue sarcoma and bone sarcomas after at least four chemotherapy cycles (under review after receiving Complete Response letter from FDA in June; NME); breast cancer with exemestane, compared to breast cancer with dalotuzumab and exemestane (Phase II; recruiting as of November); advanced head and neck cancer, NSCLC and colon cancer, with cetuximab (Phase II); pediatric patients with advanced solid tumors (Phase I; recruiting as of September); with dalotuzumab in pediatric patients with advanced solid tumors (Phase I; recruiting as of August); advanced RCC, with vorinostat (Phase I; recruiting as of October 2012); breast cancer, with dalotuzumab (Phase I: recruiting as of September); endometrial and ovarian cancers, with paclitaxel and carboplatin (Phase I; recruiting as of September 2012); advanced cancer, with MK-2206 and MK-0752 (Phase I: recruiting as of September 2012); advanced cancer, with dalotuzumab, MK-2206 and MK-0752 (Phase I: recruiting as of August 2012)
Tivozanib (ASP4130; AV-951)
Sponsor: Aveo Oncology and Astellas
Method of Action: Tyrosine kinase inhibitor; inhibits VEGF receptor 1, 2, and 3
Indications/Phase of Trial: U.S.: Advanced RCC (Registration; NDA filed September 2012); tivozanib biomarkers in solid tumors (Phase II; BATON study); stage IV metastatic colorectal cancer (mCRC), with mFOLFOX6, and compared with bevacizumab and mFOLFOX6 (Phase II; recruiting as of November); additional data as first-line therapy for advanced RCC, followed by sunitinib (Phase II; TAURUS study, enrollment initiated in October 2012); advanced solid tumors, with capecitabine (Xeloda®; Phase I; recruiting as of October)
EU: Advanced RCC (Phase III)
Trastuzumab-DM1 (T-DM1; Trastuzumab emtansine; RG3502)
Sponsor: Roche, with linker technology developed by ImmunoGen
Method of Action: Antibody-drug conjugate, consisting of the antibody trastuzumab and the chemotherapy DM1 attached via a stable linker
Indications/Phase of Trial: U.S.: HER2+, unresectable locally-advanced or mBC who have received prior treatment with Herceptin (trastuzumab) and a taxane chemotherapy (Registration; Priority review approved Nov. 7; action date Feb. 26, 2013)
EU: Marketing Authorization Application for HER2+ mBC accepted for review by European Medicines Agency
Tyverb/Tykerb (lapatinib)
Sponsor: GlaxoSmithKline
Method of Action: Human epidermal growth factor receptor-2 (Her2) and epidermal growth factor receptor (EGFR) dual kinase inhibitor
Indications/Phase of Trial: mBC with trastuzumab (Registration); breast cancer, adjuvant therapy (Phase III); Gastric cancer (Phase III); head & neck squamous cell carcinoma, resectable disease (Phase III)
Xgeva (denosumab)
Sponsor: Amgen, with commercialization by GlaxoSmithKline in countries where Amgen has no presence
Method of Action: Fully human monoclonal antibody that specifically targets a ligand known as RANKL that binds to a receptor known as RANK
Indications/Phase of Trial: Delay or prevention of bone metastases in breast cancer (Phase III); delay or prevention of bone metastases in prostate cancer (Phase III)
Approved for prevention of fractures in men with advanced prostate cancer
Rejected in April for supplemental Biologics License Application to treat men with CRPC at high risk of developing bone metastases
Yondelis® (trabectedin)
Sponsor: Johnson & Johnson; developed in collaboration with PharmaMar
Method of Action: Binds to minor groove of DNA, interfering with the cell division and gene transcription processes, as well as DNA’s repair machinery
Indications/Phase of Trial: U.S.: Locally advanced or metastatic soft tissue sarcoma excluding leiomyosarcoma and liposarcoma who have relapsed or are refractory to standard-of-care treatment (Phase III; recruiting as of November); soft tissue sarcoma, excluding liposarcoma and leiomyosarcoma (L-type sarcoma), in previously-treated patients who cannot be expected to benefit from currently available therapeutic options (Phase III; recruiting as of November); locally advanced or metastatic L-sarcoma (liposarcoma or leiomyosarcoma) who were previously treated with at least an anthracycline and ifosfamide-containing regimen, or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen, compared with dacarbazine group (Phase III; recruiting as of November); breast cancer and pediatric tumors (Phase II); Advanced malignancies and liver dysfunction (Phase I; recruiting as of November)
EU: Approved for advanced or metastatic soft tissue sarcoma, and for relapsed platinum-sensitive ovarian cancer, with DOXIL®/Caelyx®
Xtandi® Capsules (Enzalutamide; formerly MDV3100)
Sponsor: Medivation in collaboration with Astellas
Method of Action: Androgen receptor inhibitor
Indications/Phase of Trial: Prechemotherapy CRPC in patients who have failed luteinizing hormone-releasing hormone (LHRH) analog treatment only, as well as patients who have failed both LHRH analog and anti-androgen treatment. (Phase III; PREVAIL study); prostate cancer neoadjuvant therapy (Phase II); prechemo metastatic prostate cancer in Europe (Phase II; TERRAIN); prechemo metastatic and nonmetastatic prostate cancer patients in U.S. (Phase II; STRIVE); prostate cancer Hormone-naïve (Phase II; ASPIRE); prostate cancer with docetaxel (Phase I); breast cancer (Phase I)
EU: Marketing Authorization Application submitted June 2012 to European Medicines Agency, for patients with metastatic CRPC who have received docetaxel-based chemotherapy
Japan: Metastatic CRPC who have received docetaxel-based chemotherapy (Phase II)
Approved Aug. 31 for patients with metastatic CRPC who have previously received docetaxel. As a post-marketing requirement, Medivation and Astellas agreed to conduct an open-label safety study of Xtandi (160 mg/day) in patients at high risk for seizure, with data to be submitted to FDA in 2019
Menarini launches premature ejaculation drug in Singapore
DAPOXETINE
Menarini has launched dapoxetine for premature ejaculation in Singapore, having recently published a survey highlighting the rising problem of sexual dissatisfaction in the Asia-Pacific region.
The Italian drugmaker acquired Priligy (dapoxetine)from Johnson & Johnson last year and the drug is now approved in over 50 countries. It estimates that PE affects 34% of men in Singapore at some point in their lives.
READ ALL AT
Dapoxetine, marketed as Priligy (among and other brands) is the first compound developed specially for the treatment of premature ejaculation (PE) in men 18–64 years old.Dapoxetine works by inhibiting the serotonin transporter, increasing serotonin’s action at the post synaptic cleft, and as a consequence promoting ejaculatory delay. As a member of selective serotonin reuptake inhibitor (SSRI) family, dapoxetine was initially created as an antidepressant. However, unlike other SSRIs, dapoxetine is absorbed and eliminated rapidly in the body. Its fast acting property makes it suitable for the treatment of PE but not as an antidepressant.[3]
Originally created by Eli Lilly pharmaceutical company, dapoxetine was sold to Johnson & Johnson in 2003 and submitted as a new drug application to the Food and Drug Administration (FDA) for the treatment of PE in 2004. Dapoxetine has been sold in several European and Asian countries, and lately in Mexico. In the US, dapoxetine is in phase III development and expected to be marketed soon. In 2012, Menarini acquired the rights to commercialise Priligy in Europe, most of Asia, Africa, Latin America and the Middle East.
Premature ejaculation
Randomized, double blind, placebo-controlled trials have confirmed the efficacy of dapoxetine for the treatment of PE. Different dosage has different impacts on different type of PE. Dapoxetine 60 mg significantly improves the mean intravaginal ejaculation latency time (IELT) compare to that of dapoxetine 30 mg in men with lifelong PE, but there is no different in men with acquired PE. Dapoxetine, given 1–3 hours before sexual episode, prolongs IELT, increases the sense of control and sexual satisfaction in men of 18 to 64 years of age with PE. Since PE is associated with personal distress, interrelationship difficulty, dapoxetine provides help for men with PE to overcome this condition.Because lack of specific approval treatment for PE in the US and some other countries, other SSRIs such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram have been used as off label drugs to treat PE. Waldinger’s meta analysis shows that the use of these conventional antidepressants increasing IELT from two to ninefold above base line in comparison of three to eightfold when dapoxetine is used. However, these SSRIs must be taken daily in order to achieve meaningful efficacy, and the long half-life increases the risk of the drug accumulation and as a consequence increased of adverse effects such as decreasing sexual libido and causing erectile dysfunction. Dapoxetine, on the other hand, is a fast-acting SSRI. It is rapidly absorbed and eliminated from the body within a few hours. This favorable pharmacokinetics minimizes the risk of the drug’s accumulation in the body, and therefore reducing side effects.
African medicine-cyclotides as an aid during child birth
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| Oldenlandia affinis was used by native women in the Zaire as an aid during childbirth. A tea was made of the leaves and imbibed during labour. |
Cyclotides are plant-derived peptides of approximately 30 amino acids. They have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. Their unique structural features lead to exceptional stability. This and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications.
David J Craik, University of Queensland, Brisbane, Australia, whose laboratory is working over 20 years in the field, summarizes the history of cyclotides
http://www.chemistryviews.org/details/news/5012211/History_of_Cyclotides.html
more info on cyclotides
This is how it was discovered: a physician working in the Democratic Republic of Congo noticed that laboring women were drinking tea made from Oleanda affinis to induce childbirth. Theactive ingredient was the first cyclotide to be discovered. Since then, cyclotides have been shown to be antibiotic, antiviral and insecticidal.
Figure 1. Structure and sequence of the prototypic cyclotide kalata B1
Cyclotides are small disulfide-rich proteins that have the unusual feature of a cyclic backbone (hence the name cyclo – peptides). They contain six conserved cystine residues that are arranged in a cystine knot topology in which two disulfide bonds and their connecting backbone segments form an embedded ring in the structure that is penetrated by a third disulfide bond, as shown below.
Cyclotides have a range of interesting biological activities including anti-HIV and neurotensin inhibition, anti-microbial activity and insecticidal activity. They are found in a variety of tropical plants from the Rubiaceae and Violaceae families.
 |
| The structure of kalata B1 showing the distorted beta-sheet topology and the loop nomenclature enabled by the cyclic backbone. |
Cyclotides are small disulfide rich peptides isolated from plants.Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae, and Cucurbitaceae families. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.,
Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensinantagonism, trypsin inhibition, and uterotonic activities. An ability to induceuterine contractions was what prompted the initial discovery of kalata B1.
The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.
The cyclotides have been recognised as a family of novel circular proteins only in the last few years but the discovery of the first member of this family may be traced back to reports of native medicine applications in the early 1970s.
Kalata B1, was discovered because it is an active ingredient in a herbal medicine used by African women to assist childbirth . While on a Red Cross relief effort in the Congo region in the 1960s a Norwegian doctor, Lorents Gran, noted that during labour African women often ingested a tea made from leaves of the plant Oldenlandia affinis because of its uterotonic effects. The active ingredient was determined to be a peptide that was named kalata B1, after the local name for the native medicine. Subsequent in vivo studies in rats confirmed uterotonic activity of the purified peptide but it was not characterised as a macrocyclic peptide until some 20 year later.
The mid-1990�s was a key period in the discovery of macrocyclic peptides, with several independent groups discovering such peptides while screening for various biological activities and our group determining the three dimensional structure of kalata B1 . In the first fortuitous discovery Sch�pke et al., examined Viola arvensis and V. tricolor in a study aimed at the discovery of new saponins. While assaying for the usual hemolytic activity of saponins they discovered a macrocyclic peptide, violapeptide I, with hemolytic activity. At around the same time bio-assay driven screens for anti-HIV and anti-neurotensin activity led to the discovery of the circulins and cyclopsychotride A respectively.
 |
| Viola arvensis a cyclotide containing plant. Member of the violaceae family and found in temperate regions of Australia and Europe. |
With our report of the three dimensional structure of kalata B1 in 1995 and its sequence homology with the circulins and cyclopsychotride A, we became convinced that macrocyclic peptides might be more common than had earlier been thought and we began searching for other examples. Several other macrocyclic peptides were found in the late 1990s and it became clear that the peptides formed part of a family that we subsequently named the cyclotides.
Several novel cyclotide sequences have been discovered in the last few years , with the known sequences now exceeding 45 and many more currently being characterized in our laboratories. A large proportion of the new cyclotides have been discovered based on their structural properties rather than biological activities. The cyclotides are relatively hydrophobic and can be readily identified from crude plant extracts by their characteristically late elution on RP-HPLC.
The cyclotides described above, all come from plants in the Rubiaceae or Violaceae families but the prevalence of macrocyclic peptides has recently been expanded to include the Cucurbitaceae family. This is based on the discovery of the trypsin inhibitors MCoTI-I and MCoTI-II, 34 residue macrocyclic peptides, from Momordica cochinchinensis . They have no sequence homology to the previously characterized cyclotides, with the exception of the six cysteine residues, but are of a similar size and contain a cystine knot motif (Felizmenio-Quimio, 2001). The MCoTI peptides were originally isolated based on their trypsin inhibitory activity and are homologous to linear cystine knot peptides from the squash family of trypsin inhibitors such as EETI-II and CMTI.
References
Bokesch HR, Pannell LK, Cochran PK, Sowder RC, 2nd, McKee TC and Boyd MR: A novel anti-HIV macrocyclic peptide from Palicourea condensata. J. Nat. Prod. (2001) 64:249-250.
Broussalis AM, Goransson U, Coussio JD, Ferraro G, Martino V and Claeson P: First cyclotide from Hybanthus (Violaceae). Phytochemistry (2001) 58:47-51.
Claeson P, G�ransson U, Johansson S, Luijendijk T and Bohlin L: Fractionation protocol for the isolation of polypeptides from plant biomass. J. Nat. Prod. (1998) 61:77-81.
Craik DJ, Daly NL, Bond T and Waine C: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. J. Mol. Biol. (1999) 294:1327-1336.
G�ransson U, Luijendijk T, Johansson S, Bohlin L and Claeson P: Seven novel macrocyclic polypeptides from Viola arvensis. J. Nat. Prod. (1999) 62:283-286.
Gran L: Isolation of oxytocic peptides from Oldenlandia affinis by solvent extraction of tetraphenylborate complexes and chromatography on sephadex LH-20. Lloydia (1973a) 36:207-208.
Gran L: On the effect of a polypeptide isolated from “Kalata-Kalata” (Oldenlandia affinis DC) on the oestrogen dominated uterus. Acta Pharmacol. Toxicol. (1973b) 33:400-408.
Gustafson KR, Sowder II RC, Henderson LE, Parsons IC, Kashman Y, Cardellina II JH, McMahon JB, Buckheit Jr. RW, Pannell LK and Boyd MR: Circulins A and B: Novel HIV-inhibitory macrocyclic peptides from the tropical tree Chassalia parvifolia. J. Am. Chem. Soc. (1994) 116:9337-9338.
Hallock YF, Sowder RCI, Pannell LK, Hughes CB, Johnson DG, Gulakowski R, Cardellina JHI and Boyd MR: Cycloviolins A-D, anti-HIV macrocyclic peptides from Leonia cymosa. J. Org. Chem.(2000) 65:124-128.
Hernandez JF, Gagnon J, Chiche L, Nguyen TM, Andrieu JP, Heitz A, Trinh Hong T, Pham TT and Le Nguyen D: Squash trypsin inhibitors from Momordica cochinchinensis exhibit an atypical macrocyclic structure. Biochemistry (2000) 39:5722-5730.
Saether O, Craik DJ, Campbell ID, Sletten K, Juul J and Norman DG: Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1. Biochemistry (1995) 34:4147-4158.
Sch�pke T, Hasan Agha MI, Kraft R, Otto A and Hiller K: H�molytisch aktive komponenten aus Viola tricolor L. und Viola arvensis Murray. Sci. Pharm. (1993) 61:145-153.
Witherup KM, Bogusky MJ, Anderson PS, Ramjit H, Ransom RW, Wood T and Sardana M: Cyclopsychotride A, A biologically active, 31-residue cyclic peptide isolated from Psychotria Longipes. J. Nat. Prod. (1994) 57:1619-1625.
Extracting the Medicine from Traditional Chinese Medicine-Used as sedative and a painkiller in Oriental medicine
Nardostachys chinensis.
Extracting the Medicine from Traditional Chinese Medicine
Nardostachys chinensis or “Gansong” – a medicinal plant in the family Valerianaceae – is used as a sedative and a painkiller in Oriental medicine. Jun Zhou, Chinese Academy of Sciences, Kunming, and colleagues have isolated a new type of sesquieterpenoid–chalcone hybrid, containing a 2,3-dihydrofuran ring fused to an aristolane-type sesquiterpenoid and a chalcone, nardokanshone A (pictured).
- Zhang, X; Lan Z, Dong XP, Deng Y, Hu XM, Peng T, Guo P. (January 2007). “Study on the active components of Nardostachys chinensis”. Zhong Yao Cai: 38–41. PMID 17539300. Retrieved 12 June 2013.
Merck and Lupin collaborate to co-market Merck’s Pneumovax 23 Pneumococcal polysacharide vaccine for Indian market
%200.5%20mL407.GIF)
Pneumococcal polysaccharide vaccine (PPSV) — the latest version is known asPneumovax 23 (PPV-23) — is the first pneumococcal vaccine, the first vaccine derived from a capsular polysaccharide, and an important landmark in medical history. The polysaccharide antigens were used to induce type-specific antibodies that enhanced opsonization, phagocytosis, and killing of pneumococci by phagocytic cells. The pneumococcal polysaccharide vaccine is widely used in high-risk adults. As a result, there have been important reductions in the incidence, morbidity, and mortality from pneumococcal pneumoniae and invasive pneumococcal disease.
First used in 1945, the tetravalent vaccine was not widely distributed, since its deployment coincided with the discovery of penicillin. In the 1970s, Robert Austrian championed the manufacture and distribution of a 14-valent PPSV. This evolved in 1983 to a 23-valent formulation (PPSV23). A significant breakthrough impacting the burden of pneumococcal disease was the licensing of a protein conjugate heptavalent vaccine (PCV7) beginning in February 2000.
Enbrel (etanercept), Biosimilar innovator drug companies scrambling to copy
Enbrel (etanercept)
http://www.biosimilarnews.com/enbrel-patent-in-the-us
Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product.
Amgen announced the issuance of U.S. Patent No. 8,063,182 related to Enbrel (etanercept).owned by Hoffmann-la roche and licensed to Amgen (exp2028) VIA immunex
A biosimilar etanercept, manufactured in China by CP Guojian Pharmaceutical Co., Ltd. (Shanghai), is already being marketed in China as Yisaipu [3] and in Colombia as Etanar [4]. Several biotechnology companies in Asia are also developing biosimilar versions of tumor necrosis factor inhibitors. Protalix Biotherapeutics, Inc. (Carmiel, Israel) is developing a biosimilar etanercept that is expressed in plant cells [5]. Mycenax Biotech (Taiwan) has completed early-phase clinical trials of a biosimilar etanercept in Southeast Asia: a phase I trial among 24 healthy subjects in South Korea and a phase I/II trial that enrolled 18 patients with rheumatoid arthritis in Taiwan [6]. Avesthagen (Bangalore, India) has received a patent from the Indian patent office for a biosimilar etanercept [7]. In South Korea, both Celltrion (Yeonsu-gu Incheon City) and Aprogen (Daejeon) are developing a biosimilar of infliximab [8] and LG Life Sciences (Seoul) is developing biosimilars of both etanercept and infliximab to treat rheumatoid arthritis and other inflammatory diseases [9].
Drug developers:
- Avesthagen: Avent™ in clinical studies
read this doc
http://www.avesthagen.com/docs/020910pr.pdf
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- BioXpress Therapeutics: Biosimilar in active development
http://www.bioxpress.com/pipeline/
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- Cipla:Etacept, Launches biosimilar in India on April 17, at a price of Rs. 6,150 ($113.43), 30% less than the innovator product.
- read this
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- Hanwha Chemical: HD203 “scheduled for launch,” company states on its website without including a date, following submission for marketing approval to South Korea’s Korea Ministry of Food and Drug Safety following completion of Phase I and Phase III trials. Hanwha has said it will seek a partner to commercialize HD203 and a biosimilar for Herceptin (trastuzumab).
- http://www.thepharmaletter.com/file/105028/merck-co-links-with-koreas-hanwha-on-biosimilar-of-enbrel.html
………………………………………………………………………………
- LG Life Sciences: LBEC0101 completed Phase I trial in South Korea
http://www.lgls.co.kr/rd/pipeline.jsp
………………………………………………………………………………
- Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea
…………………………………………………………………………..
- Protalix Biotherapeutics: PRX-106 in preclinical studies
http://www.protalix.com/product-development/prx-106.asp
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- Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China
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Recently discontinued effort: Merck & Co. and Hanwha Chemical: Hanwha disclosed December 18, 2012, that Merck terminated agreement to develop and manufacture the biosimilar MK-8953, now called HD203, as well as market it in all countries except South Korea and Turkey, an up to $720 million deal signed June 2011.1
Nature and indication: Tumor necrosis factor (TNF) blocker for rheumatoid arthritis, polyarticular Juvenile Idiopathic Arthritis (JIA) in patients aged two years or older; psoriatic arthritis; ankylosing spondylitis; and plaque psoriasis
2012 sales: $7.963 billion (includes $4.236 billion Amgen + $3.737 billion Pfizer). Amgen markets Enbrel in U.S. and Canada under an agreement with Pfizer set to expire October 31, 2013
Patent status: Patents set to expire in EU in 2015; in U.S., 2019, 2023, 2028, and 2029
Etanercept is a fusion protein produced by recombinant DNA, which fuses a soluble human TNF receptor with an IgG1 antibody. This modified protein works by blocking TNF activity, thereby reducing their ability to cause an inflammatory response as well as severe, chronic pain and discomfort to patients. The fusion protein is protected by five different molecule Key patent families (Fig 2) and are all considered to be a constraint to generic entry until expiry. Although the patent families are owned by different patentees, Amgen have entered into licensing agreements with all parties allowing them sole distributing and marketing rights of Enbrel®.
- Public Health Service Act Sec. 262. Regulation of biological products.http://www.fda.gov/RegulatoryInformation/Legislation/ucm149278.htm
- Woodcock J, Griffin J, Behrman R, Cherney B, Crescenzi T, Fraser B, Hixon D, Joneckis C, Kozlowski S, Rosenberg A, Schrager L, Shacter E, Temple R, Webber K, Winkle H. The FDA’s assessment of follow-on protein products: a historical perspective. Nat Rev Drug Discov. 2007;6:437–442. doi: 10.1038/nrd2307. [PubMed] [Cross Ref]
- Yisaipu. http://www.cpgj-pharm.com/en/product_patient.asp?proid=22&action=intro
- Rondon F, Bautista A, Salazar JC, Casas N, Santos P, Vargas F, Marquez J. Etanar therapy in real-life patients with rheumatoid arthritis [abstract]Arthritis Rheum. 2010;62(Suppl 10):1811.
- Pipeline products. http://www.protalix.com/pipeline_products.html
- Biosimilar TuNEX® completes Phase I/II clinical trial in Taiwan, Phase I in Korea. http://www.mycenax.com.tw/webe/html/02news/news_show.aspx?page=1
- Singh K. Avesthagen gets patent for Enbrel biosimilar. Economic Times. 2010.
- Korea’s Celltrion and Aprogen in race to sell biosimilars in Japan.http://sis.windhover.com/buy/abstract.php?id=28101102003
- LG Life Sciences’ Pipeline Overview. http://thinklgls.com/rnd/pipeline
- Dr. Reddy’s Marketed Pharmaceutical Products.http://www.drreddys.com/products/bio_mproducts.html#
- TL011 in severe, active rheumatoid arthritis patients.http://clinicaltrials.gov/ct2/show/NCT01123070
- GP2013 in the treatment of RA patients refractory to or intolerant of standard therapy. http://www.clinicaltrials.gov/ct2/show/NCT01274182
- View Opportunities. http://www.sourcegenerics.com/viewAllListing.asp
- Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FE, Cookfair DL, Simon JH, Jacobs LD. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)Neurology. 1998;50:1266–1272. [PubMed]
- Casadevall N, Nataf J, Viron B, Kolta A, Kiladjian JJ, Martin-Dupont P, Michaud P, Papo T, Ugo V, Teyssandier I, Varet B, Mayeux P. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med. 2002;346:469–475. doi: 10.1056/NEJMoa011931. [PubMed] [Cross Ref]
- Schellekens H, Jiskoot W. Eprex-associated pure red cell aplasia and leachates. Nat Biotechnol. 2006;24:613–614. doi: 10.1038/nbt0606-613.[PubMed] [Cross Ref]
- Bennett CL, Luminari S, Nissenson AR, Tallman MS, Klinge SA, McWilliams N, McKoy JM, Kim B, Lyons EA, Trifilio SM, Raisch DW, Evens AM, Kuzel TM, Schumock GT, Belknap SM, Locatelli F, Rossert J, Casadevall N. Pure red-cell aplasia and epoetin therapy. N Engl J Med. 2004;351:1403–1408. doi: 10.1056/NEJMoa040528. [PubMed] [Cross Ref]
- Federal Food, Drug, and Cosmetic Act (FD&C Act) SEC. 505. [21 USC §355] New Drugs.http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/FDCActChapterVDrugsandDevices/ucm108125.htm
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products. London: European Medicines Agency; 2005.
- Committee for Medicinal Products for Human Use. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: non-clinical and clinical issues. London: European Medicines Agency; 2006.
- European Medicines Agency. Work plan for the biosimilar medicinal products working party (BMWP) 2011. London: European Medicines Agency; 2010.
- H. R. 3590–686. Patient Protection and Affordable Care Act. Title VII– Improving Access to Innovative Medical Therapies. Subtitle A–Biologics Price Competition and Innovation. Sec. 7002. Approval Pathway for Biosimilar Biological Products.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/UCM216146.pdf
- Implementation of the Biologics Price Competition and Innovation Act of 2009.http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ucm215089.htm
see details of etanercept
Etanercept
ATC (Anatomical Therapeutic Chemical Classification)
L04AA11,L04AB01
CAS registry number (Chemical Abstracts Service)
0185243-69-0
Chemical Formula
C2224-H3472-N618-O701-S36
Molecular Weight
51238
Therapeutic Categories
Immunosuppressant
Disease-modifying antirheumatic drug, DMARD
Biological response modifier, BRM
Anti-inflammatory agent
Tumor necrosis factor alpha (TNF-α) inhibitor
Chemical Name
Dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1
is made from the combination of two naturally occurring soluble human 75-kilodalton TNF receptors linked to an Fc portion of an IgG1. The effect is an artificially engineered dimeric fusion protein.
• Sandoz continues to advance biosimilar pipeline with seven Phase III trials across five molecules
• Global program underscores Sandoz’s leadership in biosimilarsHolzkirchen, Germany, June 24, 2013 – Sandoz, the global leader in biosimilars, announced it has initiated a major Phase III clinical trial with its biosimilar version of etanercept (Amgen’s Enbrel®).
Read more at
http://www.drugs.com/news/novartis-begins-enbrel-phase-iii-trial-45414.html
| Etanercept (trade name Enbrel) is a biopharmaceutical that treats autoimmune diseases by interfering with tumor necrosis factor (TNF; a soluble inflammatory cytokine) by acting as a TNF inhibitor. It has U.S. F.D.A. approval to treat rheumatoid, juvenile rheumatoid andpsoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF-alpha is the “master regulator” of the inflammatory (immune) response in many organ systems. Autoimmune diseases are caused by an overactive immune response. Etanercept has the potential to treat these diseases by inhibiting TNF-alpha. Etanercept is a fusion protein produced by recombinant DNA. It fuses the TNF receptor to the constant end of the IgG1 antibody. First, the developers isolated the DNA sequence that codes the human gene for soluble TNF receptor 2, which is a receptor that binds to tumor necrosis factor-alpha. Second, they isolated the DNA sequence that codes the human gene for the Fc end of immunoglobulin G1 (IgG1). Third, they linked the DNA for TNF receptor 2 to the DNA for IgG1 Fc. Finally, they expressed the linked DNA to produce a protein that links the protein for TNF receptor 2 to the protein for IgG1 Fc.The prototypic fusion protein was first synthesized and shown to be highly active and unusually stable as a modality for blockade of TNF in vivo in the early 1990s by Bruce A. Beutler, an academic researcher then at the University of Texas Southwestern Medical Center at Dallas, and his colleagues.[2][3][4] These investigators also patented the protein, selling all rights to its use to Immunex, a biotechnology company that was acquired by Amgen in 2002.It is a large molecule, with a molecular weight of 150 kDa., that binds to TNFα and decreases its role in disorders involving excess inflammation in humans and other animals, including autoimmune diseases such as ankylosing spondylitis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and, potentially, in a variety of other disorders mediated by excess TNFα.In North America, etanercept is co-marketed by Amgen and Pfizer under the trade name Enbrel in two separate formulations, one in powder form, the other as a pre-mixed liquid. Wyeth is the sole marketer of Enbrel outside North America excluding Japan whereTakeda Pharmaceuticals markets the drug.Etanercept is an example of a protein-based drug created using the tools of biotechnologyand conceived through an understanding afforded by modern cell biology.  |
Figure 2: Molecule Key Patents landscape
International Market
Patents protecting the various technologies of the Etanercept molecule (Fig. 2) across all five families have now expired in Europe, Canada and Australia. In Europe, SPCs and paediatric extensions were granted based on the EP0418014 (1989-09-05) and EP0939121 (1989-09-12) however the last of the paediatric extensions expired in early August, 2015. Finland has been granted a national patent disclosing the Etanercept sequence in the family with priority US40324189A (1989-09-05), which would constrain generic entry until April, 2020. Cyprus has also received a five year patent extension on a national patent set to expire in mid-2016 and would be a constraint for biosimilars entering the market there.
Although the Etanercept molecule is no longer protected in the European, Canadian or Australian markets, no biosimilar has been approved in these major markets suggesting the difficulty of developing a biosimilar which complies with the stringent regulatory pathways in place. Having said that, Merck and Samsung Bioepis (a joint venture from electronics giant Samsung and biotech firm Biogen Idec) has submitted their Etanercept biosimilar candidate SB4 to the EMA, which is currently awaiting review. If approved, it is expected that they will obtain further approval in other territories where Etanercept is no longer protected. With the regulatory approval pathways differing from country to country, Etanercept biosimilars have been approved in smaller markets including India, China and South Korea.
US Market
In the US, the ‘molecule’ patents protecting active ingredient Etanercept have all expired aside from US8,063,182 (‘182) and US8,163,522 (‘522) members from priority CH331989 (1989-09-12) owned by Roche (exclusively licensed to Amgen), which are set to expire in 2028 and 2029, respectively. These patents members disclose a portion of the Etanercept sequence, so are considered to constrain biosimilar entry until expiry. The members are continuation patents filed from US5,610,279 (another member of the same family) and while they were both filed in May, 1995, were not issued until 2011 (‘182) and 2012 (‘522). Under the 35 U.S. Code § 154, these patents received 17 year patent term from the issuing date. Since these patents were applied for in 1995 during the transitional period of the TRIPS agreement, they were not published by the USPTO until they were issued. This situation often gives rise to the term ‘submarine patents’.
Currently there is no system to link relevant patents to biologic drugs in the US as with small molecule drugs (Orange Book) which makes filing biosimilars in the US a convoluted process. While the FDA are currently working on an equivalent to the Orange Book, the ‘Purple book’, companies wishing to develop biosimilars in the US need to do considerable patent landscape searching in order to avoid infringement of any patents potentially protecting the biologic drug. In the case of US member ‘182 and ‘522, upon inspection these patents are clearly relevant to Enbrel®, however without a registry there is no easy way of making this link. The patents have been flagged in the Key Patent module in Ark due to SPCs and paediatric extensions on the equivalent EP0939121 member and litigation in the US (see below).
Currently, biologic drugs approved in the US receive a 12 year data exclusivity period and in Europe, an 8 year data exclusivity period with additional 2 year market exclusivity, starting from the market authorisation date. Enbrel® was approved in 1998 and 2000, in the US and Europe, respectively and data exclusivity protection has therefore now expired.
Development of biosimilars takes considerably longer than generic medicine making it a costly venture for generic pharmaceutical manufacturers. According to Amgen, Enbrel® was protected by US5395760 (‘760) and US5605690 (‘690) members from priority 1989-09-05 which were set to lose patent protection in 2012 and 2014, respectively. In 2004, Sandoz began developing GP2015 a biosimilar equivalent of Etanercept, investing millions of dollars in the hope that they would be ready to launch by the time all the patent protection for Enbrel® expired. Currently, GP2015 is in Phase III study in the US and European Union for patients with moderate to severe chronic plaque-type psoriasis with respect to PASI 75 response rate at Week 12.
In June 2013, Sandoz filed a suit against Amgen and Roche in the US District Court for the Northern District of California seeking declaratory judgment of non-infringement, invalidity and unenforceability of the ‘182 and ‘522 patents. Sandoz claimed a ‘case of controversy’ regarding the patents, as their research and development was based on the understanding that ‘760 and ‘690 patents members were protecting Enbrel®. With the issuing of ‘182 and ‘522 patents this has essentially delayed the prospect of an Etanercept biosimilar from entering the US market until 2029.
Amgen and Roche sought a dismissal of the proceeding due to lack of subject matter jurisdiction, which was granted. Although Sandoz appealed the decision, the Court of Appeals affirmed the dismissal, since there was no real and immediate controversy as Sandoz had not yet filed an FDA application, and they had based their suit on future events and were not able to establish “real and immediate injury or threat of future injury.”
Actavis to Launch Generic Epilepsy/Bipolar Drug
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| LAMOTRIGINE |
PARSIPPANY, N.J., July 15, 2013 (AP) — Drugmaker Actavis Inc. said Monday it’s received U.S. approval to sell a generic version of Lamictal, a tablet for treating epilepsy and bipolar disorder.
Actavis, based in Parsippany, N.J., said the Food and Drug Administration has granted approval for it to sell lamotrigine tablets in doses of 25, 50, 100 and 200 milligrams.http://www.pharmalive.com/actavis-to-launch-generic-epilepsybipolar-drug
Lamotrigine, marketed in the US and most of Europe as Lamictal /ləˈmɪktəl/ byGlaxoSmithKline, is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder. It is also used off-label as an adjunct in treating depression. For epilepsy, it is used to treat focal seizures, primary and secondary tonic-clonic seizures, and seizures associated with Lennox-Gastaut syndrome. Like many other anticonvulsant medications, Lamotrigine also seems to act as an effective mood stabilizer, and has been the first U.S.Food and Drug Administration (FDA)-approved drug for this purpose since lithium, a drug approved almost 30 years earlier. It is approved for the maintenance treatment of bipolar type I. Chemically unrelated to other anticonvulsants (due to lamotrigine’s being aphenyltriazine), lamotrigine has many possible side-effects. Lamotrigine is generally accepted to be a member of the sodium channel blocking class of antiepileptic drugs,but it could have additional actions since it has a broader spectrum of action than other sodium channel antiepileptic drugs such as phenytoin and carbamazepine and is effective in the treatment of the depressed phase of bipolar disorder, whereas other sodium channel blocking antiepileptic drugs are not. In addition, lamotrigine shares few side-effects with other, unrelated anticonvulsants known to inhibit sodium channels, which further emphasizes its unique properties. Lamotrigine is inactivated by hepatic glucuronidation.
Soliris Gets Thumbs Up From EMA’s COMP
eculizumab
CAS number 219685-50-4
Alexion’s Soliris® (eculizumab) Receives Positive Opinion from the Committee for Orphan Medicinal Products for Treatment of Neuromyelitis Optica (NMO)
Alexion Pharmaceuticals, Inc. (Nasdaq: ALXN) today announced that Soliris® (eculizumab), the company’s first-in-class terminal complement inhibitor, has received a positive opinion for orphan medicinal product designation from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) for the treatment of neuromyelitis optica (NMO), a life-threatening, ultra-rare neurological disorder. The positive opinion of the COMP has now been forwarded to the European Commission for final approval and publication in the community register. Soliris is not approved in any country for the treatment of patients with NMO
http://www.pharmalive.com/soliris-gets-thumbs-up-from-emas-comp
Soliris is a formulation of eculizumab which is a recombinant humanized monoclonal IgG2/4;κ antibody produced by murine myeloma cell culture and purified by standard bioprocess technology. Eculizumab contains human constant regions from human IgG2 sequences and human IgG4 sequences and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa.
Eculizumab (INN and USAN; trade name Soliris®) is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, progressive, and sometimes life-threatening disease characterized by excessive destruction of red blood cells (hemolysis).[1] It costs £400,000 ($US 600,000) per year per patient.[1]
Eculizumab also is the first agent approved for the treatment of atypical hemolytic uremic syndrome (aHUS), an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, leading to kidney failure, damage to other vital organs and premature death.[2][3]
In clinical trials in patients with PNH, eculizumab was associated with reductions in chronic hemolysis, thromboembolic events, and transfusion requirements, as well as improvements in PNH symptoms, quality of life, and survival.[1][4][5][6] Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),[7] the formation of blood clots in small blood vessels throughout the body,[1][3][4] including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.[7]
Eculizumab was discovered and developed by Alexion Pharmaceuticals and is manufactured by Alexion. It was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 for the treatment of PNH, and on September 23, 2011 for the treatment of aHUS. It was approved by the European Medicines Agency for the treatment of PNH on June 20, 2007, and on November 24, 2011 for the treatment of aHUS. Eculizumab is currently being investigated as a potential treatment for other severe, ultra-rare disorders
- Hillmen, Young, Schubert, P, N, J, et al (2006). “The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria”.N Engl J Med 355 (12): 1233–1243. doi:10.1056/NEJMMoa061648. PMID 16990386.
- Noris, Caprioli, Bresin, M, J, E, et al. (2010). “Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype”. Clin J Am Soc Nephrol 5: 1844–1859.
- Caprioli, Noris, Brioschi, J, M, S, et al (2006). “Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome”. Blood 108: 1267–1279.
- Hillman, Hall, Marsh, P, C, JC, et al (2004). “Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria”. N Eng J Med 350: 552–559.
- Ray, Burrows, Ginsberg, Burrows, JG, RF, JS, EA (2000). “Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient”. Haemostasis 30: 103–107.
- Kelly, Hill, Arnold, RJ, A, LM, et al (2011). “Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival”. Blood 117: 6786–6792.
- .Soliris® (eculizumab) prescribing information (2011). Cheshire, CT: Alexion Pharmaceuticals.http://www.soliris.net/sites/default/files/assets/soliris)pi.pdf.
Novartis investigational drug LDK378, a selective inhibitor of (ALK), shows a marked clinical response ….49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013
LDK378
J. Med. Chem. 2013, DOI:10.1021/jm400402q).
- CAS Number:
- 1032900-25-6
- Mol. Formula:
- C28H36ClN5O3S
- MW:
- 558.13
Novartis investigational drug LDK378, a selective inhibitor of the cancer target anaplastic lymphoma kinase (ALK), shows a marked clinical response in patients with ALK+ non-small cell lung cancer (NSCLC) during the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO) on June 3, 2013.
Doctors and patients are clamoring for more ways to fight lung cancer, the leading cause of cancer deaths in the U.S., of which NSCLC is the most common form. In March, LDK378 received Breakthrough Therapy designation from the US Food and Drug Administration (FDA). The designation is intended to expedite the development and review of drugs that treat life-threatening conditions and show improvement over available therapies.
Currently, two Phase II clinical trials are actively recruiting patients worldwide. One study focuses on patients with ALK+ NSCLC who were previously treated with chemotherapy and crizotinib (NCT01685060). The second study examines LDK378 in patients who are crizotinib-naive (NCT01685138). In addition, Phase III clinical trials are planned to begin in the coming months, aiming to enroll more than 1,100 patients with ALK+ NSCLC at sites worldwide. Novartis plans to file for approval the drug in early 2014.
Chemical Name of LDK378
5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine
Chemical Synthesis of LDK378
Technical Data of LDK378
1H NMR (400 MHz, DMSO-d6 + trace D2O) δ 8.32 (s,1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.42 (s, 1H), 6.79 (s, 1H), 4.56 – 4.48(m, 1H), 3.49 – 3.32 (m, 3H), 3.10 - 2.91 (m, 3H), 2.09 (s, 3H), 1.89 – 1.77 (m, 4H), 1.22 (d, 6H), 1.13 (d, 6H); ESMS m/z 558.1 (M + H+).
The compound LDK378, a highly selective inhibitor of ALK, has been granted “Breakthrough Therapy Designation” by the FDA for the treatment of patients with ALK-positive metastatic non-small cell lung cancer (NSCLC) who have already received treatment with crizotinib (Xalkori).
ClinicalTrials.gov. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK) (Phase 1). http://www.http://clinicaltrials.gov/show/NCT01283516; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in crizotinib naïve adult patients with ALK-activated non-small cell lung cancer (Phase 2). http://www.clinicaltrials.gov/ct2/show/NCT01685138; Accessed June 7, 2013; currently recruiting participants.
ClinicalTrials.gov. LDK378 in adult patients with ALK-activated NSCLC previously treated with chemotherapy and crizotinib (phase 2) http://www.clinicaltrials.gov/ct2/show/NCT01685060; Accessed June 7,2013; currently recruiting participants.
Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. J Clin Oncol 30, 2012 (suppl; abstr 3007).
Alice Tsang Shaw, et al., Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC; 2013 ASCO Annual Meeting; Abstract Number: 8010; Citation: J Clin Oncol 31, 2013 (suppl; abstr 8010)
Tom H. Marsilje, Wei Pei, Bei Chen, Wenshuo Lu, Tetsuo Uno, Yunho Jin, Tao Jiang, Sungjoon Kim, Nanxin Li, Markus Warmuth, Yelena Sarkisova, Fangxian Sun, Auzon Steffy, AnneMarie C. Pferdekamper, Sean B Joseph, Young Kim, Tove Tuntland, Xiaoming Cui, Nathanael S Gray, Ruo Steensma, Yongqin Wan, Jiqing Jiang, Jie Li, Greg Chopiuck, W. Perry Gordon, Allen G Li, Wendy Richmond, Johathan Chang, Todd Groessl, You-Qun He, Bo Liu, Andrew Phimister, Alex Aycinena, Badry Bursulaya, Christian Lee, Donald S Karanewsky, H Martin Seidel, Jennifer L Harris, and Pierre-Yves Michellys, Synthesis, Structure-Activity Relationships and In Vivo Efficacy of the Novel Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor LDK378 Currently In Phase 1 and 2 Clinical Trials, Journal of Medicinal Chemistry, 2013
Carlos Garcia-Echeverria, Takanori Kanazawa, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ichiro Umemura; 2, 4- di (phenylamino) pyrimidines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2004080980 A1
Greg Chopiuk, Qiang Ding, Carlos Garcia-Echeverria, Nathanael Schiander Gray, Jiqing Jiang, Takanori Kanazawa, Donald Karanewsky, Eiji Kawahara, Keiichi Masuya, Naoko Matsuura, Takahiro Miyake, Osamu Ohmori, Ruo Steensma, Ichiro Umemura, Yongqin Wan, Qiong Zhang; 2, 4-pyrimidinediamines useful in the treatment of neoplastic diseases, inflammatory and immune system disorders; WO2005016894 A1
New Drug Approvals 