Home » Biosimilar drugs (Page 4)
Category Archives: Biosimilar drugs
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
.....FOR BLOG HOME CLICK HEREFlag and hits
ORGANIC SPECTROSCOPY
SUBSCRIBE
Subscribe in a reader
Enter your email address:
Delivered by FeedBurner
Subscribe to New Drug Approvals by Email
Recent Comments
 | shivkr2 on SPSR Excellence Award 2025 – S… |
 | Bonkasaurus on Infigratinib phosphate |
 | PALOVAROTENE | ORGAN… on Palovarotene |
| Pfizer just purchase… on Temanogrel | |
| Pfizer To Cash In On… on Temanogrel |
ALIROCUMAB
ALIROCUMAB
http://www.ama-assn.org/resources/doc/usan/alirocumab.pdf
Immunoglobulin G1, anti-(human neural apoptosis-regulated proteinase 1) (human REGN727 heavy chain), disulfide with human REGN727 κ-chain, dimer
Immunoglobulin G1, anti-(human proprotein convertase subtilisin/kexin type 9
(EC=3.4.21.-, neural apoptosis-regulated convertase 1, proprotein convertase 9,
subtilisin/kexin-like protease PC9)); human monoclonal REGN727 des-448-
lysine(CH3-K107)-1 heavy chain (221-220′)-disulfide with human monoclonal
REGN727 light chain dimer (227-227”:230-230”)-bisdisulfide
Clinical Trials for Compound
| Number of clinical trials registered at clinicaltrials.gov | 30 |
Biological Sequence
| Description | Sequence |
| Alirocumab heavy chain | EVQLVESGGGLVQPGGSLRLSCAASGFTFNNYAMNWVRQAPGKGLDWVSTISGSGGTTNY ADSVKGRFIISRDSSKHTLYLQMNSLRAEDTAVYYCAKDSNWGNFDLWGRGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPS VFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELT KNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQ GNVFSCSVMHEALHNHYTQKSLSLSPG |
| Alirocumab light chain | DIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNNRNFLGWYQQKPGQPPNLLIYWASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPYTFGQGTKLEIKRTVAAPS VFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC |
1245916-14-6 CAS
C6472H9996N1736O2032S42
Alirocumab is a human monoclonal antibody designed for the treatment of hypercholesterolemia.[1]
This drug was discovered by Regeneron Pharmaceuticals and is being co-developed by Regeron and Sanofi.
When the results from Phase II trials of Sanofi and Regeneron’s proprotein convertase subtilisin kexin 9 (PCSK9) inhibitor alirocumab were presented in March, they stunned even the company representatives working on the trials. “I’m still amazed by the reduction in low-density lipoprotein cholesterol (LDL-C) that we saw with our drug,” says Bill Sasiela, vice president of cardiovascular and metabolic research at Regeneron. The monoclonal antibody (mAb) reduced LDL-C levels by up to 73% in three mid-stage trials, irrespective of baseline LDL-C levels or background treatment, offering hope for millions of patients who can’t hit the recommended cholesterol targets with statins — the standard therapies for lowering LDL-C levels in patients with cardiovascular disease. Spurred on by these results, Sanofi and Regeneron geared up into Phase III trials of the first-in-class alirocumab (also known as REGN727 and SAR236553) over the summer, and initiated the latest and largest trial — an 18,000-patient outcomes study
It is a Proprotein convertase subtilisin/kexin type 9, (also known as PCSK9) inhibitor . Phase III trials showed a 47% reduction in LDL-C. There was a high rate of adverse events with 69% experiencing side effects (most common problem was infection).
About PCSK9 PCSK9 is known to be a determinant of circulating LDL levels, as it binds to LDL receptors resulting in their degradation so that fewer are available on liver cells to remove excess LDL-cholesterol from the blood. Moreover, traditional LDL-lowering therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL-cholesterol. Blocking the PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-cholesterol.
Alirocumab is an investigational, fully-human monoclonal antibody that targets and blocks PCSK9. It is administered via subcutaneous injection. By inhibiting PCSK9, a determinant of circulating LDL-C levels in the blood, alirocumab has been shown in pre-clinical studies to increase the number of LDL receptors on hepatocytes, thereby lowering LDL-C.
The investigational agent described above is currently under clinical development and its safety and efficacy have not been fully evaluated by any regulatory authority
References
- Statement On A Nonproprietary Name Adopted By The USAN Council – Alirocumab, American Medical Association.
PARIS and TARRYTOWN, N.Y., Oct. 16, 2013 /PRNewswire via COMTEX/ — Sanofi and Regeneron Pharmaceuticals, Inc. REGN -1.73% today announced that the Phase 3 ODYSSEY MONO trial with alirocumab, an investigational monoclonal antibody targeting PCSK9 (proprotein convertase subtilisin/kexin type 9), met its primary efficacy endpoint. The mean low-density lipoprotein-cholesterol (LDL-C, or “bad” cholesterol) reduction from baseline to week 24, the primary efficacy endpoint of the study, was significantly greater in patients randomized to alirocumab, as compared to patients randomized to ezetimibe (47.2% vs. 15.6%, p<0.0001). In the trial, which employed a dose increase (up-titration) for patients who did not achieve an LDL-C level of 70 milligrams/deciliter (mg/dL), the majority of patients remained on the initial low dose of alirocumab of 75 milligrams (mg). read at
Pipeline of selected PCSK9 inhibitors
| Drug name | Companies | Modality | Clinical phase |
|---|---|---|---|
| Alirocumab (also known as REGN727 and SAR236553) | Regeneron/Sanofi | Monoclonal antibody | III |
| AMG145 | Amgen | Monoclonal antibody | II |
| LGT209 | Novartis | Monoclonal antibody | II |
| RG7652 | Roche/Genentech | Monoclonal antibody | II |
| RN316 | Pfizer | Monoclonal antibody | II |
| BMS-962476 | Bristol-Myers Squibb | Adnectin | I |
| ALN-PCS | Alnylam | RNA interference | I |
| ISIS-405879/BMS-844421 | Isis/Bristol-Myers Squibb | Antisense | Discontinued |
| PCSK9, proprotein convertase subtilisin kexin 9. | |||
OCRELIZUMAB
Ocrelizumab is a humanized anti-CD20 monoclonal antibody. It targets mature B lymphocytes[1] and hence is an immunosuppressive drug candidate. It is under development by Hoffmann–La Roche‘s subsidiary Genentech, and Biogen Idec.
It had reached Phase III clinical trials for rheumatoid arthritis[2] and lupus erythematosus,[3]and Phase II for multiple sclerosis[4] and hematological cancer.[5]
In March 2010, Roche announced the suspension of clinical trials in rheumatoid arthritis and lupus erythematosus. This step followed excess deaths due to opportunistic infections. Development for multiple sclerosis continues.[6]
In October 2010 Roche announced 24 week results from the PhII study in relapse remittingMS. The drug demonstrated a statistically significant reduction in disease activity as measured by brain lesions (measured by MRI scans) and relapse rate compared to placebo. Both doses (200 mg & 600 mg) were well tolerated.Anti-B cell therapy with rituximab has been shown to be safe and beneficial for RA treatment. Rituximab is approved and marketed for the treatment of RA in patients who have failed other therapies. Ocrelizumab, a fully human monoclonal antibody against CD20, may have less immunogenicity and less complement activation than rituximab which, theoretically, may reduce the development of drug neutralizing antibodies and infusion reactions. Here, Genovese at al report the results of a Phase I/II dose finding study of Ocrelizumab in RA patients who have failed other DMARDs (including prior TNF inhibitors).
- K. John Morrow Jr (2008-06-15). “Methods for Maximizing Antibody Yields”. Genetic Engineering & Biotechnology News (Mary Ann Liebert, Inc.). p. 36. Retrieved 2008-07-06. (Note: information included in this article only found in table present in print version of article.)
- Kausar, F; Mustafa, K; Sweis, G; Sawaqed, R; Alawneh, K; Salloum, R; Badaracco, M; Niewold, TB et al. (2009). “Ocrelizumab: a step forward in the evolution of B-cell therapy”. Expert opinion on biological therapy 9 (7): 889–95. doi:10.1517/14712590903018837.PMID 19463076.
- http://www.clinicaltrials.gov/ct2/show/NCT00539838 A Study to Evaluate Two Doses of Ocrelizumab in Patients With Active Systemic Lupus Erythematosus (BEGIN)
- http://www.clinicaltrials.gov/ct2/show/NCT00676715 A Study of the Efficacy and Safety of Ocrelizumab in Patients With Relapsing-Remitting Multiple Sclerosis.
- Hutas, G (2008). “Ocrelizumab, a humanized monoclonal antibody against CD20 for inflammatory disorders and B-cell malignancies”.Current opinion in investigational drugs (London, England : 2000) 9 (11): 1206–15. PMID 18951300.
- Katie Reid (2010-03-08). Update 2. Roche suspends arthritis treatment after deaths. Reuters. Retrieved 2010-03-08
Certolizumab pegol – FDA gave green light to UCB’s Cimzia to treat psoriatic arthritis
Certolizumab pegol
The US Food and Drug Administration has approved UCB’s Cimzia for the treatment of adults with psoriatic arthritis, the third indication approved by the agency.
The UCB’s biologic drug Cimzia is already on the market for rheumatoid arthritis and Crohn’s disease in both US and Europe. Cimzia, also known as Certolizumab pegol, is a monoclonal antibody directed against tumor necrosis factor alpha. It is a PEGylated Fab’ fragment of a humanized TNF inhibitor monoclonal antibody
read all at http://www.pharmatopics.com/2013/09/fda-gave-green-light-to-ucbs-cimzia-to-treat-psoriatic-arthritis/
Certolizumab pegol (CDP870, tradename Cimzia) is a therapeutic monoclonal antibody to tumor necrosis factor alpha (TNF-α), for the treatment of Crohn’s disease and rheumatoid arthritis, manufactured by UCB.
certolizumab pegol is a monoclonal antibody directed against tumor necrosis factor alpha. More precisely, it is a PEGylated Fab’fragment of a humanized TNF inhibitor monoclonal antibody.
Polyethylene glycol does not cross the placenta, so it should be safe in pregnancy.
Positive results have been demonstrated in two phase III trials (PRECiSE 1 and 2) of certolizumab pegol versus placebo in moderate to severe active Crohn’s disease. In addition, data from both trials suggest it is well tolerated. As yet its efficacy has not been directly compared to other anti-TNF-α agents.
Preliminary results of the RAPID 1 and 2 phase III studies were also reportedly positive.
In 2013, a phase 3 double blind randomized placebo-controlled study found significantly positive result in patient self-reported questionnaires, with rapid improvement of function and pain reduction.
On April 22, 2008, the U.S. Food and Drug Administration (FDA) approved Cimzia for use in the United States for the treatment of Crohn’s disease in people who did not respond sufficiently or adequately to standard therapy.
On June 26, 2009, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) issued a positive opinion recommending that the European Commission grant a marketing authorisation for Cimzia for the treatment of rheumatoid arthritis only – the CHMP refused approval for the treatment of Crohn’s disease. The marketing authorisation was granted to UCB Pharma SA on October 1, 2009.
Daclizumab
| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized (from mouse) |
| Target | CD25 |
DACLIZUMAB,
Daclizumab is a humanized monoclonal antibody indicated in the United States for prophylaxis of acute organ rejection in patients receiving renal transplants.
It was marketed as Zenepax, but discontinued by Roche in 2009 due to diminishing market demand for that indication. Biogen Idec is currently conducting phase III trials for daclizumab in MS. A phase III trial started in March 2010 is being conducted to determine efficacy of preventing MS relapse.
Study dosing of daclizumab is 150 mg subcutaneously once every 4 weeks versus interferon beta-1a (Avonex) 30 mg intramuscularly given once weekly for 96 to 144 weeks.
Daclizumab (Zenapax®) (molecular wt = 144 kd.) is a humanized monoclonal antibody (IgG1) produced by recombinant DNA technology. It gained FDA approval in Dec 1997. It is known by several other names including HAT (Humanized Anti-Tac), SMART anti-Tac, anti-CD25, and humanized anti-IL2-receptor. It was developed and patented by Protein Design Laboratories (Mountain View, CA) and it is marketed by Hoffman LaRoche (Nutley, NJ ).
Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. In the model below, the murine portions are shown in red and dark blue; the rest of the molecule (gray color) represents the human sequence
The study is aiming for enrollment of 1500 patients and is expected to be complete in January 2014.
more info
Daclizumab (trade name Zenapax) is a therapeutic humanized monoclonal antibody. It is used to prevent rejection in organ transplantation, especially in kidney transplants. The drug is also under investigation for the treatment of multiple sclerosis.
Daclizumab works by binding to CD25, the alpha subunit of the IL-2 receptor of T cells. The drug is marketed in the US, but not in Europe.
Uses
Prevention of organ transplants
Daclizumab is given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. These saturate the receptors and prevent T cell activation and thus prevent formation of antibodiesagainst the transplant.
Like the similar drug basiliximab, daclizumab reduces the incidence and severity of acute rejection in kidney transplantation without increasing the incidence of opportunistic infections.
Daclizumab usage may also be indicated in place of a calcineurin-inhibitor (ciclosporin or tacrolimus) during the early phase after kidney transplantation, when the kidney is recovering and vulnerable to calcineurin-inhibitor toxicity. This has been shown to be beneficial in non-heart beating donor kidney transplantation.
In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) has recommended its use be considered for all kidney transplant recipients.[citation needed]
Multiple sclerosis
In 2006 it began a Phase II clinical trial that finished in 2007 as a possible multiple sclerosis (MS) treatment. Participants were nine patients with multiple sclerosis not controlled with interferon. Daclizumab was effective in reducing lesions and improving clinical scores.[1] As of June 2013, the drug is in Phase III trials for this indication.[2]
Autoimmune diseases
Daclizumab has also been used to slow the progression of autoimmune diseases, particularly that of birdshot chorioretinopathy.[3]
Common side effects with a frequency of at least 10% include sleeplessness, tremor, headache, arterial hypertension, dyspnoea, gastrointestinal side effects and oedema. In rare cases, the drug can cause severe anaphylaxis.[4]
Daclizumab must not be administered to lactating women.[4]
History
Daclizumab was developed by PDL Biopharma, building on research at the National Institutes of Health (NIH).[5] Since December 1997, it is marketed by Hoffmann-La Roche in the US.
In April 2008, Hoffmann-La Roche submitted an application to have its marketing authorisation withdrawn in the EU for commercial reasons. The drug faced diminishing market demand, according to the company. There were no safety concerns with its use. As of January 2009, its marketing authorisation has been withdrawn and the product discontinued completely.[6][7]
- Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG (2007). “Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results”.Neurology 69 (8): 785–789. doi:10.1212/01.wnl.0000267662.41734.1f.PMID 17709711.
- ClinicalTrials.gov NCT01462318 An Immunogenicity and Pharmacokinetics (PK) Study of DAC HYP Prefilled Syringe in Relapsing Remitting Multiple Sclerosis (RRMS) (OBSERVE)
- Sobrin L, Huang JJ, Christen W, Kafkala C, Choopong P, Foster CS (2008). “Daclizumab for treatment of birdshot chorioretinopathy”. Arch Ophthalmol. 126 (2): 186–191. doi:10.1001/archophthalmol.2007.49. PMID 18268208.
- “EPAR for Zenapax”. European Medicines Agency. 2007.
- Tsurushita, N.; Hinton, P. R.; Kumar, S. (2005). “Design of humanized antibodies: From anti-Tac to Zenapax”. Methods 36 (1): 69–83.doi:10.1016/j.ymeth.2005.01.007. PMID 15848076. edit
- British National Formulary, Edition 57
- EMEA: Withdrawal of the marketing authorisation in the European Union
EMA approves biosimilar Somatropin from Biopartners Gmbh
![OMNITROPE® (somatropin [rDNA origin] injection) Structural Formula Illustration](https://i0.wp.com/images.rxlist.com/images/rxlist/omnitrope1.gif)
SOMATROPIN
The European Medicine agency has approved a biosimilar somatropin from Biopartners GMBH. Somatropin biopartner would be the third biosimilar version of somatropin the European market. Other players selling somatropin inlcude Sandoz and Roche. Sandoz sells under the brand Omnitrope, while Roche which is the innovator of somatropin sells it under the brand name NutropinAq.
READ AT
DETAILS OF OMNITROPE
Omnitrope® (somatropin-[rDNA] origin) is a polypeptide hormone of recombinant DNA origin. It has 191 amino acid residues and a molecular weight of 22,125 daltons. The amino acid sequence of the product is identical to that of human growth hormone of pituitary origin (somatropin). Omnitrope® is synthesized in a strain of. Escherichia coli that has been modified by the addition of the gene for human growth hormone. Omnitrope® Cartridge is a clear, colorless, sterile solution for subcutaneous injection. Omnitrope® for Injection is a lyophilized powder that is reconstituted for subcutaneous injection.
Figure 1: Schematic amino acid sequence of human growth hormone including the disulfide bonds
|
Each Omnitrope® Cartridge or vial contains the following (see Table 4):
Table 4. Contents of Omnitrope® Cartridges and Vial
| Product | Cartridge 5 mg/1.5 mL | Cartridge 10 mg/1.5 mL | For Injection 5.8 mg/vial |
| Component | |||
| Somatropin | 5 mg | 10 mg | 5.8 mg |
| Disodium hydrogen phosphate heptahydrate | 1.3 mg | 1.70 mg | 2.09 mg |
| Sodium dihydrogen phosphate dihydrate | 1.6 mg | 1.35 mg | 0.56 mg |
| Poloxamer 188 | 3.0 mg | 3.0 mg | – |
| Mannitol | 52.5 mg | – | – |
| Glycine | – | 27.75 mg | 27.6 mg |
| Benzyl alcohol | 13.5 mg | – | – |
| Phenol | – | 4.50 mg | – |
| Water for Injection | to make 1.5 mL | to make 1.5 mL | – |
| Diluent (vials only) | Bacteriostatic Water for Injection | ||
| Water for injection | to make 1.14 mL | ||
| Benzyl alcohol | 17 mg | ||
The European Commission has approved the first copycat version of an antibody-based drug, clearing the way for increased competition for the makers of multi-billion dollar biotechnology drugs to treat complex diseases
Tuesday’s final green light for Inflectra – which was developed by South Korea’s Celltrion and will be marketed by U.S. company Hospira – had been expected following a European Medicines Agency recommendation in June.
Hospira said the drug for treating rheumatoid arthritis and some other conditions would be launched throughout Europe “at the earliest opportunity taking into account any relevant patent protection”.
Inflectra is a so-called biosimilar version of Johnson & Johnson and Merck & Co’s Remicade.
http://www.reuters.com/article/2013/09/10/celltrion-hospira-europe-idUSL5N0H620R20130910
remicade= infliximab
Infliximab (INN; trade name Remicade) is a monoclonal antibody against tumour necrosis factor alpha (TNF-α) used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc. (formerly Centocor Biotech, Inc.) in the USA, Mitsubishi Tanabe Pharma in Japan, Xian Janssen in China, and Schering-Plough (now part of Merck & Co) elsewhere.[1] In 2013, two biosimilars were submitted for approval in Europe, by Hospiraand Celltrion Healthcare.[2]
Infliximab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of psoriasis, Crohn’s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Infliximab won its initial approval by the FDA for the treatment of Crohn’s disease in August 1998.[3]
Infliximab works by binding to TNF-α. TNF-α is a chemical messenger (cytokine) and a key part of the autoimmune reaction. In rheumatoid arthritis, infliximab seems to work by preventing TNF-α from binding to its receptor in the cell.
Infliximab is an artificial antibody. It was originally developed in mice as a mouse antibody. Because humans have immune reactions to mouse proteins, the mouse common domains were replaced with similar human antibody domains. Because the antibodies were produced from one cell grown into a clone of identical cells, it is called a monoclonal antibody. Furthermore, as a combination of mouse and human antibody amino acid sequences, it is called a chimeric monoclonal antibody.
Infliximab was developed by Junming Le and Jan Vilcek at New York University School of Medicine and developed by Centocor, (now Janssen Biotech, Inc.)[4]
In the United States, Infliximab can cost $19,000 to $22,000 a year per patient wholesale, according to Centocor.[5]
Other monoclonal antibodies targeting TNF-α are golimumab (Simponi), adalimumab(Humira), and certolizumab pegol (Cimzia). Etanercept also binds and inhibits the action of TNF-α, but is not a monoclonal antibody (it is instead a fusion of TNF-receptor and anantibody constant region).[6]
Infliximab is administered by intravenous infusion, typically at six- to eight-week intervals, at a clinic or hospital. It cannot be administered orally because the digestive system would destroy the drug.[7]
- “Remicade Becomes First Anti-TNF Biologic Therapy to Treat One Million Patients Worldwide” (Press release).Johnson & Johnson. November 6, 2007. Retrieved 2009-11-14.
- ^ George, John (June 28, 2013). “Billion-dollar biotech drug may soon have biosimilar competition”. Philadelphia Business Journal. Retrieved June 27, 2013.
- ^ “Infliximab Product Approval Information – Licensing Action”.Drugs@FDA. U.S. Food and Drug Administration (FDA). Retrieved 2009-11-14.
- ^ Knight DM, Trinh H, Le J et al. (November 1993). “Construction and initial characterization of a mouse-human chimeric anti-TNF antibody”. Mol. Immunol. 30 (16): 1443–53.doi:10.1016/0161-5890(93)90106-L. PMID 8232330.
- ^ “Priced out of pain relief; Insurers balk at high costs of promising new treatments”, Victoria Colliver, San Francisco Chronicle, May 8, 2007
- ^ Peppel, K; et al. (1991). “A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity”. J. Exp. Med. 174 (6): 1483–9.doi:10.1084/jem.174.6.1483. PMC 2119031.PMID 1660525.
- ^ Steinhilber, D; Schubert-Zsilavecz, M; Roth, HJ (2005). “Molekülstruktur und biologische Eigenschaften”. Medizinische Chemie (in German) (1 ed.). Stuttgart: Deutscher Apothekerverlag. p. 5. ISBN 3-7692-3483-9.
Biosimilars applications under review by EMA – 2013 Q2
The European Medicines Agency (EMA) is the body responsible for approval of biosimilars within the EU. A legal framework for approving biosimilars was established in 2003. Approval of biosimilars is based on an abbreviated registration process, which allows biosimilars manufacturers to provide a reduced package of information compared to originator drugs, provided they can prove ‘similarity’ to the originator or ‘reference drug’.
read all at
http://www.gabionline.net/Biosimilars/General/Biosimilars-applications-under-review-by-EMA-2013-Q2
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
…………………………………………………………………………………..
- BioXpress Therapeutics: Biosimilar in active development
http://www.bioxpress.com/pipeline/
………………………………………………………………………………………
- 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
………………………………………………………………………………….
- 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
…………………………………………………………………………………
- Shanghai CP Goujian Pharmaceutical: Etanar®, marketed in Colombia; Yisaipu, marketed in China
……………………………………………………………………………………………..
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.”
Biosimilar drugs step up complexity, by Phillip Broadwith
The first ever generic monoclonal antibody therapies have been recommended for approval in Europe. The two biosimilar versions of infliximab (Johnson & Johnson’s Remicade) have passed assessment by the European Medicines Agency’s committee for medicinal products for human use, but will need to be fully approved by the European commission before they can be marketed.
Monoclonal antibodies are significantly larger and more complex than previously approved biosimilars, which include growth hormones and erythropoietin. Proving that they are functionally similar to the original drug is therefore complex. Both manufacturers, Celltrion and Hospira, had to complete human trials to prove that their generic infliximab products were as safe and effective as Remicade in treating autoimmune diseases.
read all at
http://www.rsc.org/chemistryworld/2013/07/biosimilar-approval-steps-complexity
New Drug Approvals 
