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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
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- LG Life Sciences: LBEC0101 completed Phase I trial in South Korea
http://www.lgls.co.kr/rd/pipeline.jsp
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- Mycenax Biotech: TuNEX in Phase III clinical trials in Japan and South Korea
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- 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.”
Cabozantinib, Cometriq
Cabozantinib (marketed under the tradename Cometriq, formerly known as XL184) is asmall molecule inhibitor of the tyrosine kinases c-Met and VEGFR2, and has been shown to reduce tumor growth, metastasis, and angiogenesis.
It was developed by Exelixis Inc.
Cabozantinib was granted orphan drug status by the U.S. Food and Drug Administration(FDA) in January 2011.
Cabozantinib was approved by the U.S. FDA in November 2012 for the treatment of medullary thyroid cancer.It is currently undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, pancreatic, hepatocellular and kidney cancers.
In October 2011, cabozantinib met its primary endpoint in a phase 3 clinical trial (EXAM) conducted by Exelixis investigating its effect on progression-free survival in medullary thyroid cancer.A new drug application was submitted in the first half of 2012, and on November 29, 2012 cabozantinib was granted marketing approval by the U.S. FDA under the name Cometriq for treating patients with medullary thyroid cancer.
Grapefruit and grapefruit juice should be avoided as they may increase the concentration of the drug in the blood.
It is not yet known if Cometriq is safe and effective in children.
In 2009 a phase II study for relapsed glioblastoma multiforme reported encouraging interim results.
Positive data from clinical trials in 2011 indicate cabozantinib is beneficial in metastatic advanced prostate cancer (castration-resistant prostate cancer). 97% of patients either had stabilization or improvement in bone malignancies. The median time to disease progression was 29 weeks.
One US trial reported in May 2011: The best results were seen in patients with liver, prostate, and ovarian cancer: 22 of 29 patients with liver cancer, 71 of 100 patients with prostate cancer, and 32 of 51 with ovarian cancer experienced either partial tumor shrinkage or stable disease. Fifty-nine out of 68 patients who had bone metastases had their metastases shrink or disappear during the trial.
A pivotal trial for thyroid cancer should report interim results mid-2011.
It is undergoing clinical trials for the treatment of prostate, ovarian, brain, melanoma, breast, non-small cell lung, hepatocellular and kidney cancers.
The U.S. Food and Drug Administration approved Exelixis Inc’s cabozantinib on November 29, 2012 as a treatment for medullary thyroid cancer (MTC) that has spread to other parts of the body.
Chemical Structure of Cabozantinib L-Malate Salt (Cometriq)
Name:Cabozantinib L-Malate;Cabozantinib S-Malate; XL 184; BMS907351
Chemical Name: N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (2S)-2-Hydroxybutanedioic Acid
CAS Number: 1140909-48-3
Brand Name: Cometriq
Developer: Exelixis Inc(South San Francisco, California)
Approval Date: November 29th, 2012(US FDA)
Treatment for: Thyroid Cancer
Chemical Synthesis of Cabozantinib L-Malate Salt (Cometriq)
Reference for the Preparation of Cabozantinib L-Malate
1)St Clair Brown, Adrian; Lamb, Peter; Gallagher, William P.; Preparation of malate salts of N-[4-[[6,7-bis(methyloxy)quinolin-4-yl]oxy]phenyl]-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide and crystalline forms thereof for the treatment of cancer; PCT Int. Appl. (2010), WO 2010083414
2)Bannen, Lynne Canne; Chan, Diva Sze-ming; Chen, Jeff; Dalrymple, Lisa Esther; Forsyth, Timothy Patrick; Huynh, Tai Phat; Jammalamadaka, Vasu; Khoury, Richard George; Leahy, James William; Mac, Morrison B.;Preparation of quinolines and quinazolines as inhibitors of c-Met and other tyrosine kinases and therapeutic uses against proliferative diseases; PCT Int. Appl. (2005), WO 2005030140 A2
Synthesis Cabozantinib into two fragments, one clip from the dicarboxylic acid 1 starts, one-pot method carboxylic acid 1 and after conversion to the acid chloride-fluoroaniline ( 2 ) reaction of 3 , 3 with oxalyl chloride into the acid chloride 4 . Another fragment from the 5 and 6 obtained by condensation of 7 , 7 obtained in the reduction of the nitro 8 , 8 and 4 in alkaline conditions condensation Cabozantinib.
Generic Licensing News-SPIRAMYCIN Featured product
SPIRAMYCIN
Spiramycin is a macrolide antibiotic. It is used to treat certain types of infections that are caused by bacteria. It is most commonly used to treat infections of the lung, skin, and mouth.
Spiramycin is sometimes used to treat gonorrhea for people who are allergic to penicillin. Spiramycin is also used as an alternative agent in the treatment of toxoplasmosis during pregnancy.
Spiramycin is a macrolide antibiotic. It is used to treat toxoplasmosisand various other infections of soft tissues. Although used in Europe, Canada and Mexico,[1] spiramycin is still considered an experimental drug in the United States, but can sometimes be obtained by special permission from the FDA for toxoplasmosis in the first trimester of pregnancy.[2]
Spiramycin has been used in Europe since the year 2000 under thetrade name “Rovamycine”, produced by Rhone-Poulenc Rorer and Famar Lyon, France and Eczacibasi Ilae, Turkey. It also goes under the name Rovamycine in Canada (distributed by OdanLaboratories), where it is mostly marketed to dentists for mouth infections.
Spiramycin is a 16-membered ring macrolide (antibiotic). It was discovered in 1952 as a product of Streptomyces ambofaciens. As a preparation for oral administration it has been used since 1955, in 1987 also the parenteral form was introduced into practice. The antibacterial action involves inhibition of protein synthesis in the bacterial cell during translocation. Resistance to spiramycin can develop by several mechanisms and its prevalence is to a considerable extent proportional to the frequency of prescription in a given area. The antibacterial spectrum comprises Gram-positive cocci and rods, Gram-negative cocci and also Legionellae, mycoplasmas, chlamydiae, some types of spirochetes, Toxoplasma gondii and Cryptosporidium sp., Enterobacteria, pseudomonads and pathogenic moulds are resistant. Its action is mainly bacteriostatic, on highly sensitive strains it exerts a bactericide action. As compared with erythromycin, it is in vitro weight for weight 5 to 20 less effective, an equipotential therapeutic dose is, however, only double. This difference between the effectiveness in vitro and in vivo is explained above all by the great affinity of spiramycin to tissues where it achieves concentrations many times higher than serum levels. An important part is played also by the slow release of the antibiotic from the tissue compartment, the marked action on microbes in sub-inhibition concentrations and the relatively long persisting post-antibiotic effect. Its great advantage is the exceptionally favourable tolerance-gastrointestinal and general. It is available for parenteral and oral administration
- Spiramycin advanced consumer information | Drugs.com
- Toxoplasmosis at MayoClinic.com
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.
Hypertension- Maybe Your Blood’s too Thick
While watching the documentary Forks Over Knives I heard a physician explain that it was possible that a vegan diet may lower blood pressure by lowering the blood viscosity (thickness). He stated this in passing but to me it was earth-shaking. I have had thousands of patients with high blood pressure and am treating it on a daily basis. I have sat through countless lectures on hypertension and still to this day we do not really know what causes it. The leading explanations include increased sympathetic activity (think high adrenaline, anxiety), decrease kidney function with age, increased hormone called angiotensin II, or complex interaction of genetic factors. However all of these fail to really explain why obesity, inactivity and diet raise blood pressure.
When I heard that it could be the viscosity (thickness) of the blood I was overwhelmed by the simplicity of it. If the blood is thicker it…
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Merck releases positive clinical trial data for Alzheimer’s disease drug candidate
July 16 2013 | By Márcio Barra
Merck released this Sunday results from a Phase Ib study of its experimental Alzheimer’s disease (AD) drug MK-8931, in patients with mild to moderate AD, with the drug achieving positive results in reducing the level of β amyloid proteins.
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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
Orphan Drugs for Rare Diseases : Top Ten Most Expensive Drugs in USA
Drugs are expensive. Thousands of people take drugs that cost from $50,000 to $100,000 per year, such as the cancer drugs Provenge and Avastin and the medication for multiple sclerosis, Lemtrade. But a much smaller number of people have rare conditions that require lifesaving drugs whose prices are astronomical—up to $400,000 per year, prices that may reflect the cost of developing the medication.
A rare or orphan disease is a condition affecting 200,000 or fewer individuals in the United States. Rare diseases once were the neglected stepchild of drug makers, who wanted medicines they could sell to millions of patients. Today, conditions afflicting far smaller numbers are seeing booming interest from the industry. And more companies are taking advantage of grants, tax credits and other incentives of the Orphan Drug Act passed in 1983. In the preceding decade, only 10 drugs for rare diseases had been approved, but more than 400 were approved from 1984 through 2012.
Thinking you pay way too much for your monthly prescriptions? These amazingly expensive drugs may put things into perspective.
Soliris
Soliris has been made famous by Forbes as the world’s single most expensive drug, coming in at $409,500 a year. Soliris is used to treat paroxysmal nocturnal hemoglobinuria, a rare Marchiafava-Micheli blood disease that affects 8,000 Americans. The med generated $541 million in sales for Alexion Pharmaceuticals in 2010.
Paroxysmal nocturnal hemoglobinuria causes the breakdown of red blood cells and release of hemoglobin into the urine. The sudden, recurring attacks—which are often triggered by stress, exertion or infection—result in anemia. Little is known about the incidence of paroxysmal nocturnal hemoglobinuria, which can affect people of any age, but it’s believed to occur at a rate of about one to five per one million. The drug Soliris, made by Alexion Pharmaceuticals and approved by the Food and Drug Administration in 2007, stops the breakdown of cells. Soliris is a monoclonal antibody—a product engineered in the lab to mimic a natural substance. Studies show it leads to a dramatic improvement of symptoms and reduces the risks of complications.
Elaprase
Patients who suffer from Hunter syndrome, an inherited disease caused by a lack of the enzyme iduronate sulfatase can find relief in the recombinant form of this enzyme, but at an incredibly high price of $375,000 each year. Some estimates put its annual cost as high as $657,000. Each vial of the drug is reported to cost $4,215 each, and in the U.S. alone, the 500 Americans who suffer from Hunter syndrome spent a combined $353 million on Elaprase in 2009.
The incurable condition occurs in about one in 150,000 people, almost always males. The disorder typically appears in childhood and impairs growth and mental development. Afflicted children also have a distinct thickening of facial features. A late-onset version of Hunter syndrome is usually milder but can delay growth and damage joints, vision and hearing. Elaprase is an injected medication that replaces the missing enzyme. Manufactured by Shire, it was approved in 2006 improves patients’ ability to walk.
Naglazyme
Naglazyme is right behind Elaprase’s reported $375,000 price tag, coming in at the bargain price of just $365,000. This medication is for a rare connective tissue disorder called Maroteaux-Lamy syndrome, which is caused by a deficient enzyme that breaks down large sugar molecules called glycosaminoglycans. The condition occurs in about one of every 200,000 to 600,000 people. The deficiency causes growth retardation in early childhood in addition to heart disease. Naglazyme is made by Biomarin and was approved in 2005. The administration of the drug improves growth and joint movement, as well as range of motion and pain management.
Cinryze
Patients with hereditary angioedema (HAE) suffer from severe swelling, often in the face and airways, caused by low levels or improper function of the C1 inhibitor protein. This condition is hereditary, and there’s usually a family history, but often, deaths from hereditary angioedema go undiagnosed and reported as a sudden and premature death of a family member. This makes the condition relatively rare, and the treatment is quite expensive: an estimated $350,000 per year for Cinryze, an injectable man-made protein form of complement C1 esterase inhibitor. Cinryze maker Viropharma has mapped out yearly sales of the drug ranging from $95 million to as much as $350 million.
Folotyn
This medication is used to treat an aggressive type of cancer of the lymph system, peripheral T-cell lymphoma, which has spread throughout the body. The lymph system is comprised of white blood cells and T cells which fight viruses. There are many types of lymphoma, but T-cell lymphoma is rare, affecting about one to two people per 100,000.
Folotyn, made by Allos Therapeutics, was approved in 2009 and helps prolong survival. Typically, patients will take the drug for about six weeks, but even in that short amount of time, the bill for this treatment is staggering — around $30,000 per month. It’s given to people who have exhausted all other options for treatment and whose cancer has recurred. The drug, an injection, is thought to kill cancer cells; however studies so far have not shown that it prolongs survival. Still, Folotyn was approved as part of the FDA’s accelerated drug approval process to address the needs of people who have a poor prognosis.
Myozyme
Developed by Genzyme, Myozyme costs up to $100,000 per year for child treatment, and about $300,000 per year for adults. Myozyme was created to treat a rare and often fatal disease, Pompe, which disables the heart and skeletal muscles. Often affecting infants, most of its sufferers die in the first year, and those who do survive typically need assistance like ventilators and wheelchairs. But thanks to Myozyme, some patients can do fairly well with the disease, able to speak, walk, and feed themselves. The drama behind creating such an expensive, yet lifesaving drug, was depicted in the movie Extraordinary Measures, sharing the race against time and profit motives experienced in the drug’s development.
Acth
If you think $30,000 per month is insane, consider this: it’s a bargain compared to the approximate $115,000 per month families pay for ACTH. This drug is used to treat infantile spasms, seizures that often affect infants 4 to 6 months of age. Daily injections of ACTH are given for a period of weeks up to several months. At $23,000 per vial, patients often use 6 to 7 vials per course, and often go through two courses, which adds up to more than $300,000 in prescription drug bills. Unfortunately, ACTH is not FDA-approved to treat infantile spasms, and that means families may have trouble getting their insurance companies to pay for this mind-boggling bill.
Arcalyst
Rare genetic conditions like Familial Cold Auto-inflammatory Syndrome and Muckle-Wells Syndrome are inflammatory disorders that cause the body to develop symptoms without a known cause, including virus and illnesses, and can affect the bones, joints, and major organs, leading to deafness, kidney impairment, and vision loss. These inherited conditions impair the immune systems of sufferers, but with Arcalyst, the symptoms associated with these syndromes can be treated and even prevented. It’s even been found to help prevent gout flares, but all of this helpful treatment comes at a very high cost: a reported $250,000 per year of treatment.
Ceredase/Cerezyme
Patients with Gaucher disease, a condition that causes lumps of fat to build up in various places in the body, including the heart, brain, and spleen, suffer from the disease due to a missing enzyme. With Ceredase, made from human placentas, that enzyme can be replaced. But placentas don’t come cheap: the price of this drug is $150,000 per year. A new version, Cerezyme, came out in 1994, made with genetically engineered hamster cells, and was expected to be cheaper, but unfortunately for Gaucher disease sufferers, the price has actually gone up to $200,000 per year for the average patient. The drug has annual sales of more than a billion dollars.
Fabrazyme
Like so many other terribly expensive drugs on this list, Fabrazyme replaces a necessary enzyme in the human body. Patients with Fabry disease suffer from the lack of or faulty enzyme that is needed to metabolize lipids. Without it, lipids are not effectively broken down, and can build to harmful levels in the nervous system, cardiovascular system, eyes, and kidneys, leading to cloudiness of the cornea, increased heart attack and stroke risk, as well as an enlarged heart and impaired kidneys. It’s not hard to understand why this condition is just downright harmful, and why it’s so important to treat. Using Fabrazyme, patients can make up for their enzyme deficiency, reducing deposits throughout the body. The treatment is reported to cost $200,000 for a year of treatment, that is, if you can get it: in 2009, Fabrazyme maker Genzyme’s plant was shut down due to contamination, and is just now resolving its manufacturing problems.
Aldurazyme
Aldurazyme is used to treat a genetic enzyme condition, a far too common and expensive issue on this list. The condition in this case is Hurler syndrome, a metabolic disorder in which the lack of an enzyme keeps the body from breaking down certain sugars and proteins properly. Like Fabry disease, sugars and proteins not broken down will build up, leading to enlarged organs, breathing issues, decreased physical abilities, and more. With Aldurazyme, breathing and walking ability can be improved, but it does cost a pretty penny: $200,000 per year. The drug is usually given on a weekly basis in a clinic or hospital setting, which may incur additional costs as well.
DR ANTHONY MELVIN CRASTO
ORGANIC SPECTROSCOPY
New Drug Approvals 