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7 MAR 2013
The US Food and Drug Administration (FDA) has accepted for review AMAG Pharmaceuticals’ supplemental new drug application (sNDA) for Feraheme (ferumoxytol) injection for Intravenous (IV) use.
The sNDA filed is to expand the indication for ferumoxytol for the treatment of iron deficiency anemia (IDA) in adult patients with chronic kidney disease (CKD), who have failed or could not take oral iron treatment.
Ferumoxytol is currently indicated for oral use for the treatment of IDA in adult patients with CKD, according to the company.
The sNDA included the data from a global phase III program, which included two phase III clinical trials such as as IDA-301 (placebo comparator) and IDA-302 (active comparator).
The trials, which enrolled 1,400 patients, evaluated the use of ferumoxytol in a broad range of adult IDA patients, all of whom had failed or could not take oral iron treatment.
Both studies achieved the primary efficacy endpoints with statistically significant improvements in hemoglobin from baseline to the 35-day.
The studies, which also included patient-reported outcomes data as pre-specified secondary and exploratory endpoints, found no new safety signals, outside of those described in the current Feraheme (ferumoxytol) label, were observed with ferumoxytol treatment in these studies, claims the company.
In response to the application, the FDA said it will complete the review of Feraheme sNDA by 21 October 2013.
Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752-C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
Feraheme injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
STRUCTURE SOURCE http://chem.sis.nlm.nih.gov/chemidplus/rn/1309-38-2
Polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite. Ferumoxytol is a superparamagnetic iron oxide that is coated with a low molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl ether. The iron oxide is a superparamagnetic form of non-stoichiometric magnetite with crystal size of 6.2 to 7.3 nm. In solution, the colloidal particle of ferumoxytol has a Stokes diameter of 18-20 nm. Molecular weight is approximately 308,000
Iron oxide (Fe3O4). It is a black ore of IRON that forms opaque crystals and exerts strong magnetism. The NANOPARTICLES; and MICROSPHERES of its mineral form, magnetite, have many biomedical applications.
Ferumoxytol is the generic ingredient in one branded drug marketed by Amag Pharms Inc and is included in one NDA. There are six patents protecting this compound and one Paragraph IV challenge. Additional information is available in the individual branded drug profile pages.
This ingredient has eleven patent family members in ten countries.
There is one drug master file entry for ferumoxytol. One supplier is listed for this compound.
Launched – 2009, Anemia, iron deficiency
A superparamagnetic iron oxide (non-stoichiometric magnetite) coated with a low molecular weight semi-synthetic carbohydrate polyglucose carboxymethyl ether; USAN (OO-74) (Advanced Magnetics, Cambridge, MA, USA)
- C 7228
- Code 7228
Superparamagnetic iron oxide coated with a low molecular weight semi-synthetic carbohydrate polyglucose sorbitol carboxymethyl ether. The iron oxide is a superparamagnetic form of non-stoichiometric magnetite with crystal size of 6.2 to 7.3 nm. In solution, the colloidal particle has a Stokes diameter of 18-20 nm
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Feraheme, an iron replacement product, is a non-stoichiometric magnetite (superparamagnetic iron oxide) coated with polyglucose sorbitol carboxymethylether. The overall colloidal particle size is 17-31 nm in diameter. The chemical formula of Feraheme is Fe5874O8752C11719H18682O9933Na414 with an apparent molecular weight of 750 kDa.
Feraheme Injection is an aqueous colloidal product that is formulated with mannitol. It is a black to reddish brown liquid, and is provided in single use vials containing 510 mg of elemental iron. Each mL of the sterile colloidal solution of Feraheme Injection contains 30 mg of elemental iron and 44 mg of mannitol, and has low bleomycin-detectable iron. The formulation is isotonic with an osmolality of 270-330 mOsm/kg. The product contains no preservatives, and has a pH of 6 to 8.
Ferumoxytol is AMAG Pharmaceuticals’ lead investigational compound. In 2007, the company filed a regulatory application seeking approval in the U.S. for use as an intravenous iron replacement therapeutic in patients who may be on dialysis and are suffering from anemic chronic kidney disease (CKD). In 2009, FDA approval was assigned and the product became available on the market. A regulatory application was filed in the E.U. in 2010 for this indication and a positive opinion was received in 2012. Final E.U. approval was obtained in June 2012. In 2012, AMAG Pharmaceuticals submitted a supplemental NDA to the FDA for the treatment of patients with iron-deficiency anemia (IDA) who are not candidates for oral iron, for which they received a complete response letter in January 2014. In 2013, Takeda filed for approval for this indication in the E.U. This application was withdrawn in 2015 due to safety concerns.
In terms of clinical studies, phase II trials are underway at AMAG and at Oregon Health and Science University for use in magnetic resonance angiography (MRA). The National Cancer Institute is also conducting phase II trials for the imaging of primary high-grade brain tumors and/or cerebral metastases from lung or breast cancer. Phase I clinical trials are ongoing at Dana-Farber Cancer Institute for use in magnetic resonance imaging in pediatric and adult patients with malignant sarcoma.
The drug consists of intravenously administered bioavailable iron which allows for more efficient replenishment of the body’s iron stores than oral iron supplements, without their associated common side effects. Ferumoxytol is a blood pool agent, a true intravascular contrast agent that remains in the blood stream for an extended period of time. Based on this quality, the product may be useful as a contrast agent in a wide range of applications in MRI.
In 2008, fast track designation was received in the U.S. as a diagnostic agent for vascular-enhanced magnetic resonance imaging (VE-MRI) to improve the assessment of peripheral arterial disease in patients with known or suspected chronic kidney disease. In 2010, a license, development and commercialization agreement was established between Takeda and AMAG Pharmaceuticals in Asia Pacific countries (excluding Japan, China and Taiwan), Canada, Europe, the Commonwealth of Independent States and Turkey. However, in December 2014, both companies announced the termination of this license agreement. In 2011, orphan drug designation was assigned by the FDA for use in magnetic resonance imaging in brain metastases. This designation was assigned in 2012 for use in magnetic resonance imaging to assess, and monitor treatment of solid tumor malignancies previously diagnosed in pediatric patients (age 16 years and younger).
As announced in May 2008, we entered into a development and commercialization agreement with AMAG Pharmaceuticals, Inc. (“AMAG”) (NASDAQ:AMAG), a US biopharmaceutical company, for ferumoxytol, an intravenous iron replacement therapeutic agent being developed to treat iron deficiency anemia in CKD patients and in patients requiring hemodialysis.
Under the terms of the agreement, AMAG granted us exclusive rights to develop and commercialize ferumoxytol in the PRC, initially for CKD, and with an option to expand into additional indications. We will be responsible for the clinical development, registration, and commercialization of ferumoxytol in the PRC. We and AMAG will form a joint steering committee, with equal representation from both parties, to oversee and guide the development and commercialization of ferumoxytol in China. The agreement has an initial duration of 13 years and will be automatically renewed for a set term if minimum sales thresholds are achieved. AMAG will retain all manufacturing rights for ferumoxytol and will provide, under a separate agreement, commercial supply to us at a predetermined supply price.
Ferumoxytol was approved in June 2009 by the U.S. Food and Drug Administration to treat iron deficiency anemia in CKD patients and launched commercially in the U.S. by AMAG in July 2009. Ferumoxytol received marketing approval in Canada in December 2011 and a positive recommendation for approval from the Committee for Medicinal Products for Human Use of the European Medicines Agency in April 2012.
We have submitted the application for a registrational clinical trial for ferumoxytol to SFDA, as announced in January 2010. Once approved by the SFDA, we will commence a multi-center randomized efficacy and safety study in China with approximately 200 CKD patients, measuring the mean change in hemoglobin from baseline at Day 35 after first dose.
Ferumoxytol is a newer parenteral iron formulation but limited information is available as to its efficacy and administration. See e.g., Landry et al. (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68, 1801-1807; U.S. Pat. No. 6,599,498.
Another example of a preferred iron carbohydrate complex for use in the methods described herein is a carboxyalkylated reduced polysaccharide iron oxide complex (e.g., ferumoxytol, described in U.S. Pat. No. 6,599,498).
Another preferred iron carbohydrate complex for use in the methods described herein is a polyglucose sorbitol carboxymethyl ether-coated non-stoichiometric magnetite (e.g., “ferumoxytol”). Ferumoxytol is known in the art to be effective for treating anemia (at single unit doses lower than described herein). See e.g., Spinowitz et al. (2005) Kidney Intl 68, 1801-1807. Ferumoxytol is a superparamagnetic iron oxide that is coated with a low molecular weight semi-synthetic carbohydrate, polyglucose sorbitol carboxymethyl ether. Ferumoxytol and its synthesis are described in U.S. Pat. No. 6,599,498, incorporated herein by reference. Safety, efficacy, and pharmacokinetics of ferumoxytol are as described, for example, in Landry et al. (2005) Am J Nephrol 25, 400-410, 408; and Spinowitz et al. (2005) Kidney Intl 68, 1801-1807.
The iron oxide of ferumoxytol is a superparamagnetic form of non-stoichiometric magnetite with a crystal size of 6.2 to 7.3 nm. Average colloidal particle size can be about 30 nm, as determined by light scattering. Molecular weight is approximately 750 kD. The osmolarity of ferumoxytol is isotonic at 297 mOsm/kg and the pH is neutral. The blood half-life of ferumoxytol is approximately 10-14 hours. It has been previously reported that ferumoxytol can be given by direct intravenous push over 1-5 minutes in doses up to 1,800 mg elemental iron per minute, with maximal total dose up to 420 mg per injection. Landry et al. (2005) Am J Nephrol 25, 400-410, 408.
About Feraheme® (ferumoxytol)/Rienso
In the United States, Feraheme (ferumoxytol) Injection for Intravenous (IV) use is indicated for the treatment of iron deficiency anemia (IDA) in adult patients who have failed oral iron therapy. Feraheme received marketing approval from the FDA on June 30, 2009 for the treatment of IDA in adult chronic kidney disease (CKD) patients and was commercially launched by AMAG in the U.S. shortly thereafter.
Ferumoxytol is protected in the U.S. by five issued patents covering the composition and dosage form of the product. Each issued patent is listed in the FDA’s Orange Book. These patents are set to expire in March 2020; a request for patent term extension has been filed, which, if granted, may extend the patent term to June 2023 for one of the patents.
Ferumoxytol received marketing approval in Canada in December 2011, where it is marketed by Takeda as Feraheme, and in the European Union in June 2012 and Switzerland in August 2012, where it is marketed by Takeda as Rienso.
For additional U.S. product information, including full prescribing information, please visit www.feraheme.com.
AMAG now has five Orange Book-listed patents for ferumoxytol, with patent protection through March 2020, without patent term extension. AMAG has applied for a patent term extension for an Orange Book-listed ferumoxytol patent, which would lengthen that patent term through June 2023.
//////////Ferumoxytol, AMAG Pharmaceuticals, Phase II, 722492-56-0, Launched, 2009, Anemia, iron deficiency, 7228 , AMI-7228 , Code-7228