AMAG Pharmaceuticals Announces New Data from Ferumoxytol Pivotal Phase III Broad Iron Deficiency Ane

AMAG Pharmaceuticals Announces New Data from Ferumoxytol Pivotal Phase III Broad Iron Deficiency Anemia Program Presented at ASH

New Data from an Additional Study Exploring 1 Gram Total Dose Infusion of Ferumoxytol also Presented

LEXINGTON, Mass.--(BUSINESS WIRE)-- AMAG Pharmaceuticals, Inc. (NAS: AMAG) today announced that new data from two pivotal phase III clinical trials were presented at the American Society of Hematology's (ASH) annual meeting in Atlanta, Georgia. The phase III trials evaluated the use of ferumoxytol in subjects with iron deficiency anemia (IDA), regardless of the underlying cause of the anemia, who had failed or could not tolerate oral iron treatment. New data from an investigator-initiated study evaluating a one gram 15-minute infusion of ferumoxytol are also being presented at ASH; the current approved dosing of ferumoxytol is two 510 mg injections, three to eight days apart.

Two poster sessions highlighted the safety and efficacy data from each of the phase III clinical trials: IDA-301 and IDA-302. In addition, an oral presentation contained patient-reported outcome data from IDA-301, which demonstrated a direct correlation between the rise in hemoglobin and improvement in patient-reported measures of fatigue. Data from these two clinical trials will be the foundation for AMAG's supplemental new drug application (sNDA) in the United States.

More than 4 million Americans have iron deficiency anemia; 1.6 million of whom are estimated to have chronic kidney disease (CKD), while the other 2.4 million suffer from anemia due to other causes.¹ For these patients with anemia due to other causes, the underlying diseases or conditions causing IDA include abnormal uterine bleeding, gastrointestinal disorders, inflammatory diseases and chemotherapy-induced anemia. Many IDA patients fail treatment with oral iron due to intolerability or side effects.²

AMAG's sNDA will seek to expand the use of Feraheme® (ferumoxytol) for all adult iron deficiency anemia patients with a history of unsatisfactory use of oral iron. The company expects to submit the sNDA to the U.S. Food and Drug Administration (FDA) this month. In the United States, Feraheme is currently indicated only for the treatment of iron deficiency anemia in adult CKD patients.

IDA-301 Study and Results

IDA-301 was a double-blind, placebo-controlled trial designed to compare the safety and efficacy of a one gram intravenous (IV) course of ferumoxytol to IV saline given as placebo. In this study, 608 subjects were treated with ferumoxytol and 200 received placebo, with the demographics and all baseline parameters well balanced between the two treatment groups. The primary efficacy endpoint for U.S. regulators is the proportion of subjects who achieved a ≥ 2.0 g/dL increase in hemoglobin at any time from baseline to week 5; the primary efficacy endpoint for European Union (E.U.) regulators is the mean change in hemoglobin from baseline to week 5.

In the IDA-301 trial, ferumoxytol achieved both primary efficacy endpoints. Over 80% of study participants treated with ferumoxytol achieved an increase of ≥ 2.0 g/dL in hemoglobin compared to only 5.5% of subjects who received placebo, meeting the protocol defined measure of superiority (p<0.0001). The mean change in hemoglobin in ferumoxytol-treated subjects was 2.7 g/dL, compared to a mean 0.1 g/dL increase in subjects receiving placebo (p<0.0001).

Data from IDA-301 also showed a direct correlation between a rise in hemoglobin and improvement in subject-reported fatigue scores using the Functional Assessment of Chronic Illness Therapy (FACIT) instrument. At baseline, IDA-301 participants reported mean FACIT-Fatigue levels of 24, which are comparable to those described in the medical literature for anemic cancer patients receiving chemotherapy.³ Following a one gram course of therapy with ferumoxytol, the subjects in this study reported a significant improvement in fatigue scores (less fatigue) with a mean 12 point increase in FACIT-Fatigue scores from baseline to week 5 (p<0.05). In published literature, the U.S. mean FACIT-Fatigue score in a randomly selected group of 1,075 subjects was 40.⁴ In IDA-301, subjects treated with ferumoxytol achieved mean FACIT-Fatigue scores of 36 at week 5, close to those of the general U.S. population.

"Symptoms of anemia can have a negative impact on a patient's quality of life," said Dr. Saroj Vadhan-Raj, a principal investigator of the IDA-301 study and Professor and Chief of the Section of Cytokines & Supportive Oncology at University of Texas MD Anderson Cancer Center. "Subjects in IDA-301 treated with ferumoxytol had significant increases in hemoglobin levels and we observed a direct correlation between a rise in hemoglobin and an improvement in these subjects' measures of fatigue. Patients with iron deficiency anemia and an unsatisfactory history with oral iron have a real need for additional treatment options and the data from the studies presented at ASH suggest that ferumoxytol may have the potential to address that need."

In IDA-301, the overall rate of reported adverse events was higher in the ferumoxytol group than in the placebo group, although no new safety signals, outside of those described in the current Feraheme® (ferumoxytol) label, were observed in this study. The overall rate of serious adverse events (SAEs) was comparable between the two treatment groups, and two related SAEs of hypersensitivity, including one anaphylactic reaction, were reported in ferumoxytol-treated patients.

The patient-reported outcomes data are being presented in an oral presentation today at the ASH annual meeting. The safety and efficacy data from IDA-301 were presented in a poster session on Sunday, December 9, 2012 at the ASH annual meeting.

IDA-302 Study and Results

IDA-302 was a multicenter, open-label, active-controlled, international clinical trial designed to compare treatment between ferumoxytol and iron sucrose. Subjects were randomized 2:1 to receive a one gram IV course of either ferumoxytol (n=406) or iron sucrose (n=199), and the demographics and all baseline parameters were well balanced between the two treatment groups. The primary efficacy endpoint for U.S. regulators is the proportion of subjects who achieved a ≥ 2.0 g/dL increase in hemoglobin at any time from baseline to week 5; the primary efficacy endpoint for E.U. regulators is the mean change in hemoglobin from baseline to week 5.

In the IDA-302 trial, ferumoxytol achieved both primary efficacy endpoints. Subjects treated with ferumoxytol achieved a significantly greater mean increase in hemoglobin of 2.7 g/dL at week 5, compared to a 2.4 g/dL increase for those treated with iron sucrose (p<0.013). By week 5, 84% of ferumoxytol-treated subjects achieved a ≥ 2.0 g/dL increase in hemoglobin, compared to 81% of those treated with iron sucrose.

The overall rates of adverse events and related adverse events were comparable in ferumoxytol- and iron sucrose-treated subjects, and included many attributable to comorbid disease. However, the overall rate of SAEs, both related and unrelated as assessed by the investigator, was higher in ferumoxytol-treated subjects. The SAEs in two ferumoxytol-treated subjects were reported as related to the study drug by the investigators; these included one anaphylactoid reaction and one case of hypertension. In this study, no new safety signals, outside of those described in the current Feraheme® (ferumoxytol) label, were identified.

These data were presented in a poster session on Sunday, December 9, 2012 at the ASH annual meeting.

One Gram Total Dose Infusion Study

Dr. Michael Auerbach, Clinical Professor at Georgetown University Medical Center, presented new data at ASH from an exploratory study that evaluated the safety and efficacy of the administration of a full one gram dose of ferumoxytol as a single 15-minute infusion (the approved ferumoxytol dosing regimen is two 510 mg injections three to eight days apart). In this investigator-initiated, AMAG-supported study, which was conducted under an investigator-held investigational new drug application (IND), sixty adult subjects with IDA associated with a variety of underlying causes were studied and all received ferumoxytol. After a one-gram infusion of ferumoxytol, an increase of ≥ 2.0 g/dL in hemoglobin was reported in 58% of subjects by week 4 and 86% of subjects by week 8. The mean increase in hemoglobin from baseline was 2.1 g/dL at week 4 and 2.6 g/dL at week 8. Thirteen subjects reported mild, transient, transfusion-associated adverse events, one of which required treatment. Fourteen patients reported mild, self-limited arthralgias, myalgias and/or headache within 24-48 hours after treatment. No serious adverse events were reported in this study.

Dr. Auerbach commented, "Many patients with IDA do not benefit from oral iron therapy and suffer daily from anemia-related side effects. In this study, a full one gram course of ferumoxytol therapy was administered in a 15-minute infusion with no unexpected adverse events. Additionally, clinically meaningful improvements in hemoglobin levels were achieved in a majority of study participants after one 15-minute dose."

These data are being presented in a poster session today at the ASH annual meeting.

About AMAG

AMAG Pharmaceuticals, Inc. is a specialty pharmaceutical company that manufactures and markets Feraheme® (ferumoxytol) Injection for Intravenous (IV) use in the United States. For additional company information, please visit www.amagpharma.com.

About Feraheme® (ferumoxytol)/Rienso

In the United States, Feraheme® (ferumoxytol) Injection for Intravenous (IV) use is indicated for the treatment of iron deficiency anemia in adult chronic kidney disease (CKD) patients. Feraheme received marketing approval from the US Food and Drug Administration on June 30, 2009 and was commercially launched by AMAG in the US shortly thereafter. 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 product information, please visit www.feraheme.com.

The important safety information below is based on the United States prescribing information.

Important Safety Information About Feraheme

Indication and contraindications

Feraheme ® (ferumoxytol) Injection for Intravenous (IV) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Feraheme is contraindicated in patients with known hypersensitivity to Feraheme or any of its components.

Warnings and precautions

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Feraheme.Observe patients for signs and symptoms of hypersensitivity during and after Feraheme administration for at least 30 minutes and until clinically stable following completion of each administration.Only administer the drug when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Anaphylactic type reactions, presenting with cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported in the post-marketing experience. In clinical studies, serious hypersensitivity reactions were reported in 0.2% (3/1,726) of subjects receiving Feraheme. Other adverse reactions potentially associated with hypersensitivity (e.g., pruritus, rash, urticaria or wheezing) were reported in 3.7% (63/1,726) of subjects.

Severe adverse reactions of clinically significant hypotension have been reported in the post-marketing experience. In clinical studies, hypotension was reported in 1.9% (33/1,726) of subjects, including three patients with serious hypotensive reactions. Monitor for signs and symptoms of hypotension following each Feraheme injection. Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients should be regularly monitored for hematologic response during parenteral iron therapy, noting that lab assays may overestimate serum iron and transferrin bound iron values in the 24 hours following administration of Feraheme. As a superparamagnetic iron oxide, Feraheme may transiently affect magnetic resonance diagnostic imaging studies for up to 3 months following the last Feraheme dose. Feraheme will not affect X-ray, CT, PET, SPECT, ultrasound, or nuclear imaging.

Adverse reactions

In clinical trials, the most commonly occurring adverse reactions in Feraheme treated patients versus oral iron treated patients reported in ≥ 2% of chronic kidney disease patients were diarrhea (4.0% vs. 8.2%), nausea (3.1% vs. 7.5%), dizziness (2.6% vs. 1.8%), hypotension (2.5% vs. 0.4%), constipation (2.1% vs. 5.7%) and peripheral edema (2.0% vs. 3.2%). In clinical trials, adverse reactions leading to treatment discontinuation and occurring in 2 or more Feraheme treated patients included hypotension, infusion site swelling, increased serum ferritin level, chest pain, diarrhea, dizziness, ecchymosis, pruritus, chronic renal failure, and urticaria.

Post-marketing safety experience

The following adverse reactions have been identified during post-approval use of Feraheme. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following serious adverse reactions have been reported from the post-marketing spontaneous reports with Feraheme: life-threatening anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have occurred up to 30 minutes after the administration of Feraheme injection. Reactions have occurred following the first dose or subsequent doses of Feraheme.

For full prescribing information, please visit www.feraheme.com.

Forward-looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Any statements contained herein which do not describe historical facts, including but not limited to statements regarding: the expected timing of submission and outcome of the supplemental new drug application for the broader IDA indication are forward-looking statements which involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements.

Such risks and uncertainties include: (1) uncertainties regarding our and Takeda's ability to successfully compete in the intravenous iron replacement market both in the US and outside the US, including the EU, (2) uncertainties regarding our ability to successfully and timely complete our clinical development programs and obtain regulatory approval for Feraheme/Rienso in the broader IDA indication both in the US and outside of the US, including the EU, (3) the possibility that significant safety or drug interaction problems could arise with respect to Feraheme/Rienso, (4) uncertainties regarding the manufacture of Feraheme/Rienso, (5) uncertainties relating to our patents and proprietary rights both in the US and outside the US, and (6) other risks identified in our Securities and Exchange Commission (SEC) filings, including our Quarterly Report on Form 10-Q for the quarter ended September 30, 2012 and subsequent filings with the SEC. We caution you not to place undue reliance on any forward-looking statements, which speak only as of the date they are made.

We disclaim any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements.

AMAG Pharmaceuticals and Feraheme are registered trademarks of AMAG Pharmaceuticals, Inc.

Rienso is a registered trademark of Takeda Pharmaceutical Company Limited.

¹ U.S. Census; U.S. Renal Data System, USRDS 2010 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2010: 41-42; Fishbane, S. et al. Iron Indices in CKD in the NHANES 1998-2004. Clin J Am Soc Nephrol. 2009 January; 4(1): 57-61.
² Barton, James et al. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Medicine. 2000; 109: 27-32.
³ Cella D et al. Fatigue in Cancer Patients Compared with Fatigue in the General United States Population. Cancer 2002;94:2
⁴ Webster K et al. The functional assessment of chronic illness therapy (FACIT) measurement system: properties, applications, and interpretation. Health Qual Life Outcomes. 2003;1:79.

AMAG Pharmaceuticals, Inc.
Amy Sullivan, 617-498-3303

KEYWORDS: United States North America Massachusetts

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