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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Eli Lilly’s Profit Slides, Gets Priority Review for Ramucirumab
Eli Lilly’s third-quarter earnings fell 9 percent compared with last year, when the maker of Cymbalta and Cialis booked a sizeable revenue-sharing payment from a former drug developer partner.
The Indianapolis company beat Wall Street expectations for the quarter and narrowed its earnings forecast for the year.
Lilly also said Wednesday that the U.S. Food and Drug Administration will give its stomach cancer treatment ramucirumab a priority review, which means the drugmaker will learn about its fate inside of eight months rather than a year, which is the norm.
read at
http://www.dddmag.com/news/2013/10/eli-lillys-profit-slides-gets-priority-review
cut paste old article
Eli Lilly and Co. announced that results from the Phase 3 REGARD trial of ramucirumab (IMC-1121B) as a single agent in patients with advanced gastric cancer who have had disease progression after initial chemotherapy were published today in The Lancet. REGARD is the first Phase 3 study with either a single-agent biologic or an anti-angiogenic therapy to show improved overall survival and progression-free survival in advanced gastric cancer patients.
READ ALL AT
Ramucirumab (IMC-1121B)[1] is a fully human monoclonal antibody (IgG1) being developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF inangiogenesis.
Ramucirumab is being tested in several phase III clinical trials for the treatment of metastatic gastric adenocarcinoma,[2] non-small cell lung cancer,[3] among other types of cancer. On September 26, 2013 Eli Lilly announced that its Phase III study for ramucirumab failed to hit its primary endpoint on progression-free survival among women with metastatic breast cancer.[4][5]
This drug was developed by ImClone Systems Inc. It was isolated from a native phage display library from Dyax.
- Statement On A Nonproprietary Name Adopted By The USAN Council – Ramucirumab, American Medical Association.
- ClinicalTrials.gov NCT01170663 A Study of Paclitaxel With or Without Ramucirumab in Metastatic Gastric Adenocarcinoma (RAINBOW)
- ClinicalTrials.gov NCT01168973 A Study in Second Line Non Small Cell Lung Cancer
- ClinicalTrials.gov NCT00703326 Phase III Study of Docetaxel + Ramucirumab or Placebo in Breast Cancer
- Fierce Biotech. “In another stinging setback, Eli Lilly’s ramucirumab fails PhIII breast cancer study”. Retrieved 27 September 2013.
Positive Review For Gilead’s Hep C Drug Sofosbuvir
Sofosbuvir
Isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]amino]propanoate
http://www.ama-assn.org/resources/doc/usan/sofosbuvir.pdf –for cas no
The U.S. Food and Drug Administration (FDA) has issued a positive review for a highly anticipated hepatitis C drug from Gilead Sciences, saying the pill cures more patients in less time than currently available treatments.
The agency posted its review of Gilead’s sofosbuvir online ahead of a meeting Friday where government experts will vote on whether to recommend the drug’s approval.
old article cut paste
Jun. 7, 2013– Gilead Sciences, Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted priority review to the company’s New Drug Application (NDA) for sofosbuvir, a once-daily oral nucleotide analogue inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The FDA grants priority review status to drug candidates that may offer major advances in treatment over existing options. Gilead filed the NDA for sofosbuvir on April 8, 2013, and FDA has set a target review date under the Prescription Drug User Fee Act (PDUFA) of December 8, 2013.
The data submitted in this NDA support the use of sofosbuvir and ribavirin (RBV) as an all-oral therapy for patients with genotype 2 and 3 HCV infection, and for sofosbuvir in combination with RBV and pegylated interferon (peg-IFN) for treatment-naïve patients with genotype 1, 4, 5 and 6 HCV infection.
Sofosbuvir is an investigational product and its safety and efficacy have not yet been established.
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
Sofosbuvir (formerly PSI-7977 or GS-7977) is an experimental drug candidate for the treatment of hepatitis C.[1] It was discovered at Pharmasset and then acquired for development by Gilead Sciences. It is currently in Phase III clinical trials.[2]
Sofosbuvir is a prodrug that is metabolized to the active antiviral agent 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate.[3]
Sofosbuvir is a nucleotide analogue inhibitor of the hepatitis C virus (HCV) polymerase.[4] The HCV polymerase or NS5B protein is a RNA-dependent RNA polymerase critical for the viral cycle.
Sofosbuvir is being studied in combination with pegylated interferon and ribavirin, with ribavirin alone, and with other direct-acting antiviral agents.[5] It has shown excellent clinical efficacy when used either with pegylated interferon/ribavirin or in interferon-free combinations. In particular, combinations of sofosbuvir with NS5A inhibitors, such as daclatasvir or GS-5885, have shown sustained virological response rates of up to 100% in people infected with HCV.[6]
Data from the ELECTRON trial showed that a dual interferon-free regimen of sofosbuvir plus ribavirin produced a 24-week post-treatment sustained virological response (SVR24) rate of 100% for previously untreated patients with HCV genotypes 2 or 3.[7][8]
Data presented at the 20th Conference on Retroviruses and Opportunistic Infections in March 2013 showed that a triple regimen of sofosbuvir, ledipasvir (formerly GS-5885), and ribavirin produced a 12-week post-treatment sustained virological response (SVR12) rate of 100% for both treatment-naive patients and prior non-responders with HCV genotype 1.[9]Gilead has developed a sofosbuvir + ledipasvir coformulation that is being tested with and without ribavirin.
- Sofia, M. J.; Bao, D.; Chang, W.; Du, J.; Nagarathnam, D.; Rachakonda, S.; Reddy, P. G.; Ross, B. S. et al. (2010). “Discovery of a β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus”. Journal of Medicinal Chemistry 53 (19): 7202–7218. doi:10.1021/jm100863x. PMID 20845908. edit
- “PSI-7977″. Gilead Sciences.
- Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H. M. M.; Bao, D.; Chang, W.; Espiritu, C. et al. (2010). “Mechanism of Activation of PSI-7851 and Its Diastereoisomer PSI-7977″. Journal of Biological Chemistry 285 (45): 34337–34347.doi:10.1074/jbc.M110.161802. PMC 2966047. PMID 20801890. edit
- Alejandro Soza (November 11, 2012). “Sofosbuvir”. Hepaton.
- Tom Murphy (November 21, 2011). “Gilead Sciences to buy Pharmasset for $11 billion”. Bloomberg Businessweek.
- http://www.gilead.com/pr_1757156
- AASLD: PSI-7977 plus Ribavirin Can Cure Hepatitis C in 12 Weeks without Interferon. Highleyman, L. HIVandHepatitis.com. 8 November 2011.
- Nucleotide Polymerase Inhibitor Sofosbuvir plus Ribavirin for Hepatitis C. Gane, E et al. New England Journal of Medicine 368:3444. January 3, 2013.
- CROI 2013: Sofosbuvir + Ledipasvir + Ribavirin Combo for HCV Produces 100% Sustained Response. Highleyman, L. HIVandHepatitis.com. 4 March 2013.
Monoclonal antibody (mAbs) 2013
2013——-29 monoclonal antibody (mAbs) drugs are in Phase III clinical development.
While around 350 therapeutic mAbs are currently in clinical development globally, only 28 had entered active Phase 2/3 or Phase 3 studies as of January 2013, Additionally one mAb mixture was under evaluation in Phase III.
Historically, mAbs that target antigens relevant to cancer have comprised approximately 50% of the mAb clinical pipeline,
but in 2013 the picture has changed: 66% or 19 of the antibodies to watch in 2013 are for non-cancer indications.
The non-cancer mAbs include alirocumab (Regeneron; Sanofi, hypercholesterinemia);
AMG 145 (Amgen, hypercholesterinemia),
epratuzumab (UCB, SLE),
gantenerumab (Roche; Alzheimer’s disease),
gevokizumab (Xoma/Servier, Non-infectious uveitis),
itolizumab (Biocon, Plaque psoriasis), ixekizumab (Eli Lilly and Co., psoriasis),
lebrikizumab (Roche/Genentech, rheumatoid arthritis),
mepolizumab (GSK, Asthma, COPD etc.),
ocrelizumab (Roche/Genentech, multiple sclerosis),
reslizumab (Teva, Eosinophilic asthma), romosozumab (Amgen, Postmenopausal osteoporosis),
sarilumab (Regeneron; Sanofi, rheumatoid arthritis),
secukinumab (Novartis, rheuma, psoriasis),
sirukumab (Janssen R&D LLC, rheumatoid arthritis),
solanezumab (Eli Lilly and Co., Alzheimer’s disease),
tabalumab (Eli Lilly and Co., rheuma, SLE)
and
vedolizumab (Millenium, Ulcerative colitis; Crohn disease).
The mixture of actoxumab and bezlotoxumab (MK-3415A, Merck & Co.) is being evaluated in two Phase 3 studies as a treatment for Clostridium difficile infection.
The ten cancer mAbs are:
elotuzumab (Bristol-Myers Squibb, Abbott, multiple myeloma),
farletuzumab (Morphotek, ovarian cancer),
inotuzumab ozogamicin (Pfizer; UCB, ALL, NHL),
naptumomab estafenatox (Active Biotech, renal cell carcinoma),
necitumumab (ImClone LLC, NSCL),
nivolumab (Bristol-Myers Squibb, NSCL, renal cell carcinoma),
obinutuzumab (Roche/Genetech, Diffuse large B cell lymphoma, CLL, NHL),
onartuzumab (Roche/Genetech, NSCL cancer; gastric cancer),
racotumomab (CIMAB; Laboratorio Elea S.A.C.I.F. y A, NSCL),
and ramucirumab (ImClone LLC, Gastric; liver, breast, colorectal, NSCL cancers).
Antibody
Sihuan Pharma’s clinical study application for oncology drug Pirotinib accepted by CFDA
The China Food and Drug Administration (CFDA) has accepted Sihuan Pharmaceutical’s application for clinical trial approval for its Pirotinib, a Category 1.1 innovative oncology drug developed by the company’s drug R&D team.
By developing Pirotinib, Sihuan Pharma has demonstrated its capability for the oncology products market. The company holds the largest cardio-cerebral vascular (CCV) drug franchise in China’s prescription market.
The new drug is a second generation (pan-HER) inhibitor intended to treat patients with lung and breast cancer.http://www.pharmaceutical-technology.com/news/newssihuan-pharmas-clinical-study-application-oncology-drug-pirotinib-accepted-cfda?WT.mc_id=DN_News
VERCIRNON – GSK1605786A (formerly CCX282-B) Anti-inflammatory intended to treat Crohn’s disease and inflammatory bowel disease
http://www.ama-assn.org/resources/doc/usan/vercirnon.pdf
|
vercirnon
|
|
| Trade Name: | Traficet-EN |
| Synonym: | CCX282-B, GSK1605786, GSK 1605786 |
- C22H21ClN2O4S
- Average mass: 444.931091
4-(2-(4-(tert-butyl)phenylsulfonamido)-5-chlorobenzoyl)pyridine 1-oxide
698394-73-9 [RN]
Anti-inflammatory intended to treat Crohn’s
disease and inflammatory bowel disease
GSK1605786A (formerly CCX282-B) targets chemokine receptor CCR9, which is expressed selectively on intestinal lymphocytes and dendritic cells. CCR9 mediates migration of immune cells to the intestine, and blockade of the receptor inhibits migration.
GSK1605786A is being studied in CD at a dose of 500 mg by mouth once daily or 500 mg by mouth twice daily versus placebo. Final data is anticipated to be collected mid-2012 for a study evaluating efficacy over a 12-week treatment period.
A study reviewing maintenance of remission is expected to be complete in July 2014 and a long-term safety study is scheduled for completion in July 2015.
GSK-1605786 (CCX-282; Traficet-EN), a selective antagonist of the CC chemokine receptor (CCR9), is being developed by GlaxoSmithKline plc under license from ChemoCentryx Inc for the potential treatment of inflammatory bowel disease, including Crohn’s disease and celiac disease. CCR9 is a tissue-specific lymphocyte trafficking molecule that selectively attracts both B- and T-cells to the small gut. Inhibition of CCR9 by GSK-1605786 may inhibit B- and T-cell entry to the small gut and ameliorate inflammation while leaving immune function at other anatomical sites unaffected. GSK-1605786 was assessed as a treatment for moderate-to-severe Crohn’s disease in the phase II/III PROTECT-1 trial and as a treatment for celiac disease in a phase II trial. Data suggest that GSK-1605786 is efficacious in patients with Crohn’s disease with the advantage of being orally bioavailable.
BAYER- sPRM (BAY 1002670) Vilaprisan is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids
http://www.who.int/medicines/publications/druginformation/issues/Proposed-List_109.pdf str is available in this link
20,20,21,21,21-pentafluoro-17-hydroxy-11β-[4-
(methanesulfonyl)phenyl]-19-nor-17α-pregna-4,9-dien-3-one
progesterone receptor antagonist
BAY 1002670, vilaprisan
1262108-14-4
C27H29F5O4S, 544.574
http://www.who.int/medicines/publications/druginformation/issues/Proposed-List_109.pdf str is available in this link
Bayer has also made good progress in the development of new treatment options for patients with gynecological diseases: sPRM (BAY 1002670) is a novel oral progesterone receptor modulator that holds the promises of long-term treatment of patients with symptomatic uterine fibroids. Based on promising early clinical data the initiation of a Phase III study is planned for mid-2014.
A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor. A characteristic that distinguishes such substances from receptor full agonists (such as progesterone) and full antagonists (such as mifepristone) is that their action differs in different tissues (agonist in some while antagonist in others). This mixed agonist/antagonist profile of action leads to selective stimulation or inhibition progesterone-like action in different tissues and furthermore raises the possibility of dissociation of desirable therapeutic effects from undesirable side effects in synthetic progesterone receptor drug candidates
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Copanlisib (BAY 80-6946), Bayer’s novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor
Copanlisib (BAY 80-6946)
1032568-63-0, cas no
MW: 480.5262
In oncology, Copanlisib (BAY 80-6946), a novel, oral phosphatidylinositol-3 kinases (PI3K) inhibitor, was selected for accelerated development. Copanlisib demonstrated a broad anti-tumor spectrum in preclinical tumor models and promising early clinical signals in a Phase I study in patients with follicular lymphoma. A Phase II study in patients with Non-Hodgkin’s lymphoma is currently ongoing.
PI3K inhibitor BAY 80-6946
A phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity. PI3K inhibitor BAY 80-6946 inhibits the activation of the PI3K signaling pathway, which may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis and dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents.
The U.S. Food and Drug Administration approved Adempas (riociguat) to treat adults with two forms of pulmonary hypertension.
October 8, 2013 — The U.S. Food and Drug Administration today approved Adempas (riociguat) to treat adults with two forms of pulmonary hypertension.
Pulmonary hypertension is caused by abnormally high blood pressure in the arteries of the lungs. It makes the right side of the heart work harder than normal. In its various forms, pulmonary hypertension is a chronic, progressive, debilitating disease, often leading to death or need for lung transplantation
read all at
http://www.drugs.com/newdrugs/fda-approves-adempas-pulmonary-hypertension-3927.html
In the area of pulmonary hypertension Adempas (Riociguat) is the first member of a novel class of compounds – so-called ‘soluble guanylate cyclase (sGC) stimulators’ – being investigated as a new and specific approach to treating different types of pulmonary hypertension (PH). Adempas has the potential to overcome a number of limitations of currently approved treatments for pulmonary arterial hypertension (PAH) and addresses the unmet medical need in patients with chronic thromboembolic pulmonary hypertension (CTEPH). It was approved for the treatment of CTEPH in Canada in September 2013, making it the world’s first drug approved in this deadly disease.
Riociguat has already shown promise as a potential treatment option beyond these two PH indications. An early clinical study was conducted in PH-ILD (interstitial lung disease), a disease characterized by lung tissue scarring (fibrosis) or lung inflammation which can lead to pulmonary hypertension, and, based on positive data, the decision was taken to initiate Phase IIb studies in PH-IIP (idiopathic pulmonary fibrosis), a subgroup of PH-ILD. Moreover, scientific evidence was demonstrated in preclinical models that the activity may even go beyond vascular relaxation. To prove the hypothesis Bayer is initiating clinical studies in the indication of systemic sclerosis (SSc), an orphan chronic autoimmune disease of the connective tissue affecting several organs and associated with high morbidity and mortality. If successful, Riociguat has the potential to become the first approved treatment for this devastating disease.
synthesis
Generic Name: Riociguat
Trade Name: Adempas
Synonym: BAY 63-2521
CAS number: 625115-55-1
Chemical Name: Methyl N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate
Mechanism of Action: soluble guanylyl cyclase (sGC) stimulator
Date of Approval: October 8, 2013(US)
Indication: Pulmonary Hypertension
Company: Bayer AG
1)J. Mittendorf.; S. Weigand.; C. Alonso-Alija.; E. Bischoff.; A. Feurer.; M. Gerisch.; A. Kern.; A. Knorr.; D. Lang.; K. Muenter.; M. Radtke.; H. Schirok.; K.-H. Schlemmer.; E. Stahl.; A. Straub.; F. Wunder.; J.-P. Stasch. Discovery of Riociguat (BAY 63-2521): A Potent, Oral Stimulator of Soluble Guanylate Cyclase for the Treatment of Pulmonary Hypertension, ChemMedChem. 2009, 4, 853-865.
2)Cristina Alonso-Alija, Bayer Ag, Erwin Bischoff, Achim Feurer, Klaus Muenter, Elke Stahl, Johannes-Peter Stasch, Stefan Weigand, Carbamate-substituted pyrazolopyridines, WO2003095451 A1
3)Franz-Josef Mais, Joachim Rehse, Winfried Joentgen, Konrad SIEGEL, Process for preparing methyl methylcarbamate and its purification for use as pharmaceutically active compound,US20110130410
4)Claudia Hirth-Dietrich, Peter Sandner, Johannes-Peter Stasch, Andreas Knorr, Degenfeld Georges Von, Michael Hahn, Markus Follmann, The use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc), WO 2011147810A1
5)Li Liang, Li Xing-zhou, Liu Ya-dan, Zheng Zhi-bing, Li Song, Synthesis of riociguat in treatment of pulmonary hypertension, Chinese Journal of Medicinal Chemistry(Zhongguo Yaowu Huaxue Zazhi), 21(2),120-125; 2011
Jens Ackerstaff, Lars BÄRFACKER, Markus Follmann, Nils Griebenow, Andreas Knorr, Volkhart Min-Jian Li, Gorden Redlich, Johannes-Peter Stasch, Stefan Weigand, Frank Wunder, Bicyclic aza heterocycles, and use thereof, WO2012028647 A1
2)Claudia Hirth-Dietrich, Peter Sandner, Johannes-Peter Stasch, Andreas Knorr, Degenfeld Georges Von, Michael Hahn, Markus Follmann, The use of sGC stimulators, sGC activators, alone and combinations with PDE5 inhibitors for the treatment of systemic sclerosis (SSc), WO 2011147810A1
Jin Li, Xiaoyu Yang, Jingwei ZHU, Minmin Yang, Xihan Wu, Method for synthesizing 1-(2-fluorobenzyl)-1H -pyrazolo[3,4-b]pyridin -3-formamidine hydrochloride, WO2013086935 A1
veerareddy Arava, Surendrareddy Gogireddy, An expeditious synthesis of riociguat, A pulmonary hypertension drug, Der Pharma Chemica, 2013, 5(4):232-239
cut paste from my earlier post
RIOCIQUAT
CAS NO 625115-55-1
Methyl N-[4,6-Diamino-2-[1-[(2-fluorophenyl)methyl]-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-pyrimidinyl]-N-methyl-carbaminate
9 APRIL2013
Bayer has been boosted by the news that regulators in the USA are fast-tracking the German group’s investigational pulmonary arterial hypertension riociguat.
The US Food and Drug Administration has granted priority review to the New Drug Application for riociguat, which Bayer filed in February on both sides of the Atlantic for PAH and a related condition, inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The FDA bestows a priority review on medicines that offer major advances in care or that provide a treatment where no adequate therapy exists. The agency aims to complete its assessment within eight months from the submission of the NDA, rather than the standard 12 months.
Riociguat (BAY 63-2521) is a novel drug that is currently in clinical development by Bayer. It is a stimulator of soluble guanylate cyclase (sGC). At the moment Phase III clinical trialsinvestigate the use of riociguat as a new approach to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) andpulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of a novel class of sGC stimulators
The submissions are based on two Phase III studies and riociguat, the first member of a novel class of compounds called stimulators of soluble guanylate cyclase (sGC), met its primary endpoint in both trials, a change in exercise capacity after 12- or 16 weeks respectively. The drug was generally well tolerated, with a good safety profile.
If approved, riociguat would be going up against Actelion’s Tracleer (bosentan) and Gilead Sciences/GlaxoSmithKline’s Letairis/Volibris (ambrisentan). Actelion, which has dominated the PAH market, has already filed its follow-up to Tracleer, Opsumit (macitentan).
GSK and Genmab seek alternative approval for leukaemia drug Arzerra
Arzerra
GlaxoSmithKline and Genmab A/S have announced the submission of leukaemia drug Arzerra to the European Medicines Agency (EMA) for a variation in marketing authorisation.
The companies are seeking authorisation for the drug to be used in combination with an alkylator-based therapy for treatment of Chronic Lymphocytic Leukemia (CLL) patients who have not received prior treatment and are inappropriate for fludarabine-based therapy.
READ ALL AT
Ofatumumab(trade name Arzerra, also known as HuMax-CD20) is a human monoclonal antibody (for the CD20 protein) which appears to inhibit early-stage B lymphocyte activation. It is FDA approved for treating chronic lymphocytic leukemia that is refractory to fludarabine and alemtuzumab (Campath) and has also shown potential in treating Follicular non-Hodgkin’s lymphoma, Diffuse large B cell lymphoma, rheumatoid arthritis and relapsing remitting multiple sclerosis. Ofatumumab has also received conditional approval in Europe for the treatment of refractory chronic lymphocytic leukemia. This makes ofatumumab the first marketing application for an antibody produced by Genmab, as well as the first human monoclonal antibody which targets the CD20 molecule that will be available for patients with refractory CLL.
Chronic lymphocytic leukemia (CLL) is a slowly progressing cancer of the blood and bone marrow. Arzerra (ofatumumab) has been approved by the FDA for treating CLL.
Patients with CLL whose cancer is no longer being controlled by other forms of chemotherapy can be prescribed Arzerra.
People older than fifty are mainly affected by CLL. A group of white blood cells known as B-cells that are part of the body’s immune system is the source of CLL. Every year, about ¼ of people diagnosed with CLL die from the disease.
Arzerra is an anti-CD20 monoclonal antibody that targets a membrane-proximal (which means close to the cell surface), small loop epitope, which is a portion of a molecule to which an antibody binds, on the CD20 molecule on B-cells. This epitope isn’t similar to binding sites that are targeted by other CD20 antibodies that are currently available. The CD20 molecule is highly expressed in most B-cell malignancies, making it a key target in CLL therapy.
MECHANISM OF ACTION:
Binding specifically to both the small and large extracellular loops of the CD20 molecule, Arzerra is an anti-CD20 monoclonal antibody. The CD20 molecule is expressed on normal B lymphocytes (pre-B- to mature B-lymphocyte) and on B-cell CLL. The CD20 molecule isn’t internalized following antibody binding and it isn’t shed from the cell surface. The Fc domain of ofatumumab mediates immune effector functions to result in B-cell lysis in vitro, while the Fab domain binds to the CD20 molecule. Complement-dependent cytotoxicity and antibody-dependent, cell-mediated cytotoxicity has been suggested as the possible mechanisms of cell lysis.
Products receive accelerated approval based on a surrogate endpoint, such as a reduction in the size of the tumor or decrease in the number of cancerous white cells or in an enlarged spleen or lymph nodes. These indirect measures for clinical outcomes are considered reasonably likely to predict that the drug will allow patients to live with fewer side effects of a disease or to live longer. Arzerra was approved under the FDA’s accelerated approval process, which allows earlier approval of drugs that meet unmet medical needs.
To confirm that the addition of Arzerra to standard chemotherapy delays the progression of the disease, the manufacturer of this medication is currently conducting a clinical trial in CLL patients. This is because the accelerated approval process requires further study of the drug.
Epratuzumab
Epratuzumab
Epratuzumab is a humanised anti-CD22 monoclonal antibody under investigation (clinical development phase III) for its efficacy in SLE. CD22 is a B cell specific surface protein that is considered to be involved in B cell function.
| Expected indication | Systemic lupus erythematosus |
| R&D stage | Phase 3 ongoing (started in December 2010) |
| Next milestone | Phase 3 results (H1 2014) |
| Quick facts |
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Epratuzumab is a humanized monoclonal antibody. Potential uses may be found inoncology and in treatment of inflammatory autoimmune disorders, such as lupus (SLE).[1][2] The manufacturers in August 2009 announced success in early trials against SLE.[3]
Epratuzumab binds to the glycoprotein CD22 of mature and malignant B-cells.
- Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties Clinical Cancer Research Vol. 9, September 1, 2003 free full text
- Dose-Fractionated Radioimmunotherapy in Non-Hodgkin’s Lymphoma Using DOTA-Conjugated, 90Y-Radiolabeled, Humanized Anti-CD22 Monoclonal Antibody, Epratuzumab Clinical Cancer Research Vol. 11, July 15, 2005 free full text
- Reuters: UCB and Immunomedics Announce Positive Results for Epratuzumab Phase IIb Study in Systemic Lupus Erythematosus (SLE)
Epratuzumab is a humanized IgG1 antibody that acts as an antagonist of the CD22 receptor present on B cells. UCB is currently enrolling patients for the 2 Phase III trials, EMBODY-1 and EMBODY-2. The primary objective of both studies is to measure the percent of subjects meeting treatment response criteria at week 48 among those patients with moderate to severe SLE. Epratuzumab is dosed at either 600 mg per week or 1200 mg every other week administered over four 12-week treatment cycles.
The cumulative dose for both treatment arms is 2400 mg for each of the 4-week dosing periods. The estimated primary completion date is January 2014 for both EMBODY-1 and EMBODY-2. –
UCB pipeline. UCB Web site. www.ucb.com/rd/pipeline/new-development/epratuzumab. Published July 10, 2010. Accessed June 18, 2011
Brussels (Belgium), June 13th 2013, 0700 CEST – UCB today announced new data from an open-label extension (SL0008) of the EMBLEM™ phase 2b study evaluating the long-term effects of epratuzumab treatment in adult patients with moderate-to-severe systemic lupus erythematosus (SLE). The primary outcome of the open-label extension was to assess the safety of epratuzumab in patients with SLE.4
Relative to the 12 week, double-blind, placebo-controlled EMBLEM™ study, data from the open-label, long-term extension identified no new safety or tolerability signals.1 In addition, relative to EMBLEM™ baseline values, secondary outcome data indicated that the efficacy of epratuzumab as measured by reduction in disease activity was maintained over two years.2 Secondary outcome data also indicated that relative to EMBLEM™ baseline values, treatment over two years with epratuzumab was associated with decreases in corticosteroid use in patients receiving >7.5 mg/day.1 These data were presented this week at the European League Against Rheumatism 2013 Congress in Madrid, Spain.
Epratuzumab, licensed from Immunomedics Inc. (NASDAQ: IMMU), is an investigational medicine and the first CD-22/B-Cell receptor (BCR) targeted monoclonal antibody to be evaluated in clinical studies for the treatment of SLE. Also known as lupus, SLE is a complex, systemic autoimmune disease that affects many different organ systems, including the skin, joints, lungs, kidneys and blood.3,5
“In EMBLEM™, a dose-ranging, phase 2b study, reduction in disease activity was observed in patients treated with epratuzumab,” said Professor Daniel J Wallace MD, Clinical Professor of Medicine, Cedars-Sinai Medical Center, California, US. “This double-blind study had a relatively short 12-week, placebo-controlled, treatment period and it was important to accumulate long-term data on epratuzumab in the treatment of SLE. The phase 2b extension study adds new two year open-label data on epratuzumab to that already available from the 12-week, randomized, controlled study.”
EMBLEM™ was designed to identify a suitable dosing regimen for epratuzumab.6 A total of 227 patients with moderate-to-severe SLE received either: placebo, epratuzumab cumulative dose of 200 mg (100 mg every other week), 800 mg (400 mg every other week), 2400 mg (600 mg weekly), 2400 mg (1200 mg every other week) or 3600 mg (1800 mg every other week).3,6 In the open-label extension 203 patients from any arm of the EMBELM™ study received 1200 mg epratuzumab at weeks 0 and 2 of 12-week cycles.1,2,7
Data on epratuzumab presented at EULAR 2013
Evaluation of the safety profile of long-term epratuzumab treatment in patients with moderate-to-severe SLE1
Safety variables were primary outcome measures in SL0008 and included duration of exposure, adverse events, infusion reactions and infections.
Exposure to epratuzumab was a median 845 days over a median 10 treatment cycles. Adverse events (AEs) caused discontinuation in 29 (14.3%) patients. The most common serious AEs were SLE flare (3.4%), lupus nephritis (2%) and symptomatic cholelithiasis (1.5%). The most common infections/infestations were urinary tract infection (24.6%) and upper respiratory tract infection (23.2%). There were no opportunistic infections and no patterns of specific serious or severe infections.
Evaluation of long-term efficacy of epratuzumab as measured by reduction in disease activity in patients with moderate-to-severe SLE2
Secondary outcome measures in SL0008 included efficacy as measured by reduction in disease activity, and assessed by: British Isles Lupus Assessment Group (BILAG) improvement, SLE disease activity index (SLEDAI) score, Physician Global Assessment (PGA) score and combined treatment response defined as BILAG improvement without worsening, no SLEDAI worsening and no PGA worsening, relative to EMBLEM™ baseline.
The median BILAG total score was 25.0 at EMBLEM™ baseline and 9.0 at week 108. The score was 14.0 at SL0008 screening. Median SLEDAI score was 12.0 at EMBLEM™ baseline and 4.0 at week 108. The score was 10.0 at SL0008 screening. The median PGA score was 50.0 at EMBLEM™ baseline and 17.5 at week 108 with a score of 31.0 at SL0008 screening.
The proportion of patients achieving the combined treatment response was 32.5% at SL0008 screening (n=203) and 60.3% at week 108 (n=116).
Effect of corticosteroid use of long-term epratuzumab treatment in patients with moderate-to-severe SLE1
Corticosteroid doses were monitored throughout SL0008 and was a secondary outcome measure.
Median corticosteroid dose at EMBLEM™ baseline and SL0008 screening was 10.0 mg/day. At week 116, this was 5 mg/day (n=112). Data indicated that treatment over two years with epratuzumab was associated with decreases in corticosteroid use in patients receiving >7.5 mg/day with a corresponding increase in the proportion of patients receiving lower doses or no longer receiving corticosteroids.
The proportion of patients requiring 7.5-20 mg/day and >20 mg/day decreased (49.8% and 10.8% at baseline and 33.9% and 8.0% respectively, at week 116) and the proportion of patients receiving >0–7.5mg/day or no longer receiving corticosteroids increased (33.5% and 5.9% at baseline and 45.5% and 12.5% respectively, at week 116).
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