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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Antifungal drugs-Antibiotics
Antifungal drugs-Antibiotics
by Parasuraman S, Senior Lecturer at AIMST University, Malaysia on Oct 20, 2013
Health Canada approves Levemir® FlexTouch® prefilled insulin pen for the treatment of type 1 and type 2 diabetes
MISSISSAUGA, ON, Oct. 18, 2013 /CNW/ – Novo Nordisk today announced that Health Canada has approved Levemir® FlexTouch®, a disposable prefilled insulin pen containing Levemir® (insulin detemir). Levemir® FlexTouch® has been designed to improve ease of use for insulin administration and to help decrease barriers to good treatment adherence for Canadians living with type 1 and type 2 diabetes mellitus (diabetes).
The approval was also announced at the 2013 Vascular Conference in Montreal, Quebec.
Health Canada approves Levemir® FlexTouch® prefilled insulin pen for the treatment of type 1 and type 2 diabetes
http://www.pharmalive.com/health-canada-approves-levemir-flextouch
Actelion wins crucial FDA approval for next-gen lung disease drug Opsumit
MACITENTAN
N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N’-propylsulfamide, CAS NO 441798-33-0
Late on Friday the FDA came through with an approval for Actelion’s pulmonary arterial hypertension (PAH) drug Opsumit (macitentan), its next-gen successor to the franchise drug Tracleer.
Read more: Actelion wins crucial FDA approval for next-gen lung disease drug Opsumit – FierceBiotech http://www.fiercebiotech.com/story/actelion-wins-crucial-fda-approval-next-gen-lung-disease-drug-opsumit/2013-10-18#ixzz2i7tDhpZT
Subscribe at FierceBiotech
Macitentan (Opsumit® )is a novel dual endothelin receptor antagonist that resulted from a tailored drug discovery process. Macitentan has a number of potentially key beneficial characteristics – i.e., increased in vivo preclinical efficacy vs. existing ERAs resulting from sustained receptor binding and tissue penetration properties. A clinical pharmacology program indicated a low propensity of macitentan for drug-drug interactions.
Macitentan is an investigational drug being studied for the treatment of pulmonary arterial hypertension. It acts as a dualendothelin receptor antagonist and is being developed by Actelion.[1] A Phase III clinical trial was successfully completed in 2012.[2]
on 22 October 2012 – Actelion (SIX: ATLN) announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) seeking approval for macitentan (Opsumit®) for the treatment of patients with pulmonary arterial hypertension
Actelion’s experimental lung drug macitentan prolonged overall survival by more than a third according to detailed study data, which the company hopes will convince investors it has a viable follow-up product to secure its commercial future.
Europe’s largest standalone biotech company wants the drug, which treats pulmonary arterial hypertension — a disease that causes high blood pressure in the arteries of the lungs — to replace blockbuster Tracleer.
Tracleer currently makes up 87 percent of sales but loses patent protection in 2015 and has also seen its market share eroded by Gilead’s Letairis.
Pharmacokinetics
Macitentan has an active metabolite, ACT-132577, which is an oxidative depropylation product. Both macitentan and ACT-132577 are mainly excreted in form of hydrolysis products via urine (about 2/3 of all metabolites) and faeces (1/3).[3]
Co-administration of ciclosporin has only a slight effect on the concentrations of macitentan and its active metabolite, whilerifampicin decreases the area under the curve (AUC) of the drug’s blood plasma concentration by 79%, and ketoconazoleapproximately doubles it. This corresponds to the finding that macitentan is mainly metabolised via the liver enzyme CYP3A4.[4]
- ^ Bolli, M. H.; Boss, C.; Binkert, C.; Buchmann, S.; Bur, D.; Hess, P.; Iglarz, M.; Meyer, S.; Rein, J.; Rey, M.; Treiber, A.; Clozel, M.; Fischli, W.; Weller, T. (2012). “The Discovery of N-[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-N′-propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist”. Journal of Medicinal Chemistry 55 (17): 7849–7861. doi:10.1021/jm3009103. PMID 22862294. edit
- ^ “Macitentan”. Actelion. Retrieved 22 August 2012.
- ^ Bruderer, S.; Hopfgartner, G. R.; Seiberling, M.; Wank, J.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2012). “Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans”. Xenobiotica 42 (9): 901–910.doi:10.3109/00498254.2012.664665. PMID 22458347. edit
- ^ Bruderer, S.; Äänismaa, P. I.; Homery, M. C.; Häusler, S.; Landskroner, K.; Sidharta, P. N.; Treiber, A.; Dingemanse, J. (2011).“Effect of Cyclosporine and Rifampin on the Pharmacokinetics of Macitentan, a Tissue-Targeting Dual Endothelin Receptor Antagonist”. The AAPS Journal 14 (1): 68–78. doi:10.1208/s12248-011-9316-3. PMC 3282010. PMID 22189899. edit
External links
Actelion Ltd
Actelion Ltd is a biopharmaceutical company with its corporate headquarters in Allschwil/Basel, Switzerland. Actelion’s first drug Tracleer®, an orally available dual endothelin receptor antagonist, has been approved as a therapy for pulmonary arterial hypertension. Actelion markets Tracleer through its own subsidiaries in key markets worldwide, including the United States (based in South San Francisco), the European Union, Japan, Canada, Australia and Switzerland. Actelion, founded in late 1997, is a leading player in innovative science related to the endothelium – the single layer of cells separating every blood vessel from the blood stream. Actelion’s over 2,400 employees focus on the discovery, development and marketing of innovative drugs for significant unmet medical needs. Actelion shares are traded on the SIX Swiss Exchange (ticker symbol: ATLN) as part of the Swiss blue-chip index SMI (Swiss Market Index SMI®).
Characterization of the “hygroscopic” properties of active pharmaceutical ingredients
Characterization of the “hygroscopic” properties of active pharmaceutical ingredients.
Source
SSCI, Inc., West Lafayette, IN, USA. ann.newman@aptuit.com
http://www.ncbi.nlm.nih.gov/pubmed/17630643
Abstract
The amount of water vapor taken up by an active pharmaceutical ingredient (API) as a function of relative humidity is routinely evaluated to characterize and monitor its “hygroscopicity” throughout the drug development process. In this minireview we address the necessity of going beyond the measurement of water vapor sorption isotherms to establish the various mechanisms by which solids interact with water and the important role played by the crystalline or amorphous form of the solid. Practical approaches for choosing experimental conditions under which water vapor sorption should be measured, including the pre-treatment of samples and the time allowed to reach an equilibrium state are presented. With the assistance of a flowchart, we provide a basis for the systematic examination of samples to establish the likely mechanisms of sorption and the indicators pointing toward future problems with physical and chemical instabilities. Finally, we present strategies for managing materials that might be susceptible to the detrimental effects of water vapor sorption.
(Copyright) 2008 Wiley-Liss, Inc.
NovoEight (turoctocog alfa) Receives Approval from the FDA
Bagsværd, Denmark, 16 October 2013 – Today, Novo Nordisk announced that the U.S. Food and Drug Administration (FDA) has approved its Biologics License Application (BLA) for recombinant coagulation factor VIII, Novoeight.
The FDA approved Novoeight for use in adults and children with hemophilia A for:
- Control and prevention of bleeding
- Perioperative management
- Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
http://www.drugs.com/newdrugs/novoeight-turoctocog-alfa-receives-approval-fda-3931.html
turoctocog alfa (NN7008)
old clip
Novo Nordisk recently announced the company has submitted the regulatory application to the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for its turoctocog alfa (NN7008) for prevention and treatment of bleeding in people with hemophilia A.
The decision for submission was based on results from the guardian trials consisting of over 200 people with hemophilia A, making guardian the largest pre-registration clinical trial program for hemophilia A. The trials contained previously treated adults and children with severe hemophilia A.
Turoctocog alfa is a third-generation recombinant coagulation factor VIII drug, designed to increase reliability, safety and portability for patients with hemophilia A.
“We are very excited about having reached this goal. Turoctocog alfa represents a new treatment alternative for people with hemophilia A and is one of the first important outcomes of the hemophilia research strategy we embarked upon in 2006,” Mads Krogsgaard Thomsen, executive vice president and chief science officer of Novo Nordisk said in a news release.
The company said that in the next few months, it plans to submit applications for regulatory approval in other countries as well.
Hemophilia A is estimated to affect 500,000 people worldwide, and is extremely under-diagnosed in developing countries.
ema clip
On 19 September 2013, the Committee for Medicinal Products for Human Use(CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product NovoEight 250, 500, 100, 1500, 2000 or 3000 IU, powder and solvent for solution for injection, intended for the treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor-VIII deficiency).The applicant for this medicinal product is Novonordisk. It may request are-examination of the CHMP opinion, provided it notifies the European Medicines Agency in writing of its intention within 15 days of receipt of the opinion.
The active substance of NovoEight is turoctocog alfa, human recombinant factor VIII that enables the temporary substitution of the endogenous coagulation factor VIII in haemophilia A patients. The benefits with NovoEight are its ability to prevent and treat the bleeds in previously treated patients with severe haemophilia A. The most common side effects are increase in hepatic enzymes and injection-site reaction.
A pharmacovigilance plan for NovoEight will be implemented as part of themarketing authorisation.
The approved indication is:
Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor-VIII deficiency).
It is proposed that NovoEight be prescribed by physicians experienced in the treatment of haemophilia A. It is proposed that treatment should be initiated under the supervision of a doctor experienced in the treatment of haemophilia.
Detailed recommendations for the use of this product will be described in thesummary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.
The CHMP, on the basis of quality, safety and efficacy data submitted, considers there to be a favourable benefit-to-risk balance for NovoEight and therefore recommends the granting of the marketing authorisation.
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
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. | |||
New Drug Approvals 