Status: approved; marketed; withdrawn in Europe in Dec. 2008

Organizations involved:

Amgen Inc. – Manuf.; R&D; Tech.; USA mark.

Kirin Pharm., Ltd. – R&D; Tech.; Japan mark.

Fresenius Medical Care N.A. – USA mark.

Amgen-Dompe Biotec S.p.A. – Europe mark.

Columbia University – Tech.; Patent dispute

Cross ref.: See the Erythropoietin Products entry and the other EPO product entries.

Description: Darbepoetin alfa or Aranesp is an aqueous formulation of a recombinant erythropoiesis stimulating protein closely related to human EPO expressed in Chinese hamster ovary (CHO) cells. Darbepoetin alfa is a 165-amino acid glycoprotein that differs from recombinant human EPO by having two amino acid substitutions, and in its glycosylation, containing 5 N-linked oligosaccharide chains, while recombinant EPO (e.g., in Epogen, Procrit, Eprex, NeoRecormon and Dynepo) contains 3 chains. The two additional N-glycosylation sites result from amino acid substitutions in the EPO peptide backbone. These additional carbohydrate chains increase the approximate molecular weight of the glycoprotein to 37,000 Daltons (37 kDa) and improve the metabolic stability of the molecule. Aranesp maintains its level in the blood approximately three times longer than EPO, allowing less-frequent dosing (fewer injections; allowing patients and caregivers to spend less time with injection visits).

Aranesp is formulated as a sterile preservative-free solution for intravenous or subcutaneous administration. Aranesp is packaged in single-dose 1 mL vials containing 25, 40, 60, 100, 150, 200, 300 and 500 µg/mL of Aranesp. Aranesp is marketed in two formulations containing one of two different stabilizers – Albumin (Human) and polysorbate 80 (Tween 80). The polysorbate 80 solution contains 0.05 mg polysorbate 80, 2.12 mg sodium phosphate monobasic monohydrate, 0.66 mg sodium phosphate dibasic anhydrous, and 8.18 mg sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.2 ± 0.2. This product is labeled as “Albumin Free.” The albumin-stabilized solution contains 2.5 mg Albumin (Human), 2.23 mg sodium phosphate monobasic monohydrate, 0.53 mg sodium phosphate dibasic anhydrous, and 8.18 mg sodium chloride in Water for Injection, USP (per 1 mL) at pH 6.0 ± 0.3. The dating period for Aranesp containing Albumin (Human) is 36 months and for Aranesp containing polysorbate 80 is 24 months from the date of manufacture when stored at 2-8˚C (refrigerated). The date of manufacture is defined as the date of final sterile filtration of the final formulated product.

Nomenclature: EPO, darbo- [BIO]; Aranesp [TR]; darbepoetin alfa [FDA USAN INN]; Nespo [TR Europe]; [30-L-asparagine,32-L-thronine,87-L-valine,88-L-asparagine,90-L-threonine]erythropoietin (human) [CAS]; 209810-58-2 [CAS RN]; novel erythropoiesis stimulating protein [SY]; NESP [SY; TR in Japan]; epoetin alfa, darb- [SY]; NDC 55513-006-01 and NDC 55513-002-04 [NDC]

Companies.: Aranesp was developed and is manufactured by Amgen, Inc., CBER/FDA est. no. 1080. The protein is manufactured at Amgen’s facility in Thousand Oaks, CA. The final formulated product is filled, labeled, and packaged at Amgen’s facility in Juncos, Puerto Rico. Dompe Biotec S.p.A. originally marketed Darbepoetin in Europe under the trade name Nespo, with Dompe merging into Amgen in Oct. 2007.

[Note, Aranesp and several other Amgen products were actually developed through Kirin-Amgen, a joint venture company formed in 1984 50% owned by Amgen and Kirin, with exclusive manufacturing, patent and marketing rights granted to Amgen in the U.S. (and other companies in certain other territories), Amgen (and other companies in other territories) paying Kirin-Amgen unspecified royalties on sales, and with Kirin-Amgen reimbursing Amgen for R&D expenses. However, most sources treat Aranesp, Epogen and other Kirin-Amgen products as though they originate from Amgen].

In Dec. 1998, Ortho Biotech (Johnson & Johnson) lost a dispute with Amgen over marketing rights to Darbepoetin alfa. An arbitration panel ruled that marketing rights for Darbepoetin alfa belong solely to Amgen, i.e., that the original 1985 agreement between the two companies (See Epogen/Procrit entry) to market EPO did not extend to Darbepoetin alfa.

Amgen is currently constructing a second facility at its Puerto Rico site for the manufacture of Epogen and Aranesp. The planned expansion will double the square footage of the PR facilities from 500,000 to one million square feet.

In Oct. 2006, Fresenius Medical Care Holdings Inc. (FMC-NA), the U.S. subsidiary of Fresenius Medical Care AG & Co. KgaA (Fresenius AG), concluded an exclusive supplier deal with Amgen, which will be the sole supplier of EPO products to Fresenius for use in its U.S.-based dialysis centers (i.e., Fresenius will only use Epogen and Aranesp). Fresenius holds about 35% of the U.S. dialysis market (with DaVita having about 30%), and likely administers a comparable percentage of EPO products (Epogen and Aranesp) for treatment of U.S. kidney failure patients. The agreement runs from Oct. 1, 2006 to Dec. 31, 2011. The companies will also explore collaborations to develop new product formulations to further enhance standards of care. Deals such as this will be a major obstacle to Mircera, presuming it enters the U.S. market and breaks Amgen’s U.S. EPO product monopoly (see the Mircera entry). Fresenius can terminate this agreement, if a competitor offers a better product (so far, Mircera is the only near-term EPO product, and has only proven noninferiority); or there is a significant change in the reimbursement of for EPO products (which seems likely). As discussed in the Market section of the EPO Products entry above, dialysis centers, particularly large chains such as Fresenius than can negotiate significant discounts, are reimbursed a fixed fee for EPO treatment, with EPO products being a significant profit center.

Manufacture: Darbepoetin alfa was originally manufactured by culture of transformed Chinese hamster ovary (CHO-K1) cells using roller bottle cell culture technology, like EPO alfa (Epogen, Procrit, Eprex), not more modern bioreactor-based methods. Amgen converted manufacture to a more modern bioreactor process in 2008. In so doing, Amgen had to change the Master Cell Bank, which altered the entire process for manufacturing of Aranesp. The EMEA/EU required Amgen to provide substantial data from an analytical characterization component all the way through a Phase III study, even including a 1,000 patient post-market study. Thus, this comparability testing was almost identical to what other comopanies have done to get biosimilar EPO approved.

Darbepoetin alfa is constitutively expressed by the CHO cells into the culture medium. In process controls during cell culture include cell density, viability, pH, pCO2, pO2, glucose, total protein, and Darbepoetin alfa concentration. Purification involves chromatographic and filtration steps. Levels of excipients in the culture media and formulation were selected to prevent adsorption and minimize aggregation of darbepoetin alfa induced by shear and agitation stress. Unspecified raw materials of animal origin are used during serial cultivation and expansion of CHO cells in adherent and suspension cultures.

FDA class: Biologic BLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20010917; BLA, first approval; Indication = anemia associated associated with chronic renal failure (dosing every two weeks)

Date = 20020719; BLA supplement; Indications: = treatment of anemia in cancer chemotherapy patients (weekly dosing); dating period for product containing Albumin (Human) extended from 24 to 36 months; and three new dosage strengths (150 µg, 300 µg and 500 µg) for the Albumin (Human)-containing formulation

Date = 20060327; BLA supplement; Indication = approval of every-three-week dosing and new starting dosage

Date = 20070309; BLA supplement; Indication = updating of the product insert/labeling, including a black box warning (see the Status and Trials sections below)

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 4/7/2006]

Aranesp is indicated for the treatment of anemia associated with chronic renal failure, including patients on dialysis and patients not on dialysis, and for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy.

Status: Aranesp is exempt from CBER/FDA lot release requirements.

In Jan 2005, a warning was added to Aranesp labeling after studies with two other EPO products marketed primarily in Europe, Eprex and NeoRecormon (see related entries) revealed major fatal thrombotic events, including blood clots and death, when doctors used at doses higher than recommended. These effects had not been observed in Aranesp trials.

On May 6, 2005, Amgen filed a supplemental BLA seeking approval of Aranesp administration every three weeks for treatment of chemotherapy-induced anemia in patients with non-myeloid malignancies. If approved, Aranesp will be the first therapy indicated in the U.S. for once every three week dosing in the treatment of anemia in these patients.

European Union (EU) approval was granted to Dompe Biotec on June 8, 2001 for the treatment of anaemia in chronic kidney failure, including patients on and not yet on dialysis; and on Aug. 28, 2002 EU approval was granted for treatment of anemia in adult cancer patients with solid tumors (non-hematological malignancies) receiving chemotherapy. In Sept. 2004, EU supplemental approval was granted for extended Aranesp dosing intervals to once-every-three-weeks in the treatment of anemia in adult cancer patients with non-myeloid malignancies who are receiving chemotherapy and up to once-per-month administration in the treatment of anemia in chronic kidney disease patients not on dialysis. This extended dosing (from once every two weeks) simplifies the treatment process and improves management of anemia in chemotherapy patients. This extended dosing was perceived as likely to undercut the potential impact of competition from CERA, a long-acting EPO product from Hoffmann-La Roche Ltd. (see related entry).

In March 2006, a sBLA was approved for every-three-week dosing of Aranesp to treat chemotherapy-induced anemia in patients with non-myeloid malignancies, making Aranesp the only erythropoiesis-stimulating agent approved for three-week administration. The Aranesp label now includes a recommended starting dose of 500 µg once every-three-weeks in addition to a starting dose of 2.25 µg/kg once-a-week.

In Oct. 2006, FDA sent Amgen an approvable letter informing the company of the need for a new trial of de novo once-every-two-week and maintenance once-monthly dosing regimens for chronic kidney disease patients with anemia not on dialysis. Amgen countered that it would ask the FDA to consider additional data on the new doses that was not available when it filed for supplemental approval in 2005. Aranesp continues to be the only erythropoiesis-stimulating protein approved in the U.S. and EU for weekly and once-every-three-week administration.

On Jan. 26, 2007, Amgen issued a letter to oncologists alerting them that Aranesp should not be used off-label for treatment of anemai associated with cancer (not anemia associated with chemotherapy drug toxicity), because a trial had shown Aranesp to be ineffective and potentially dangerous for these uses. For further information, see the Trials section below.

In April 2007, Aranesp was approved and launched in Japan under the name NESP injection for treatment of kidney failure/dialysis.

In March 2007, the product insert/labeling was revised, and Amgen issued a “Dear Healthcare Professional” letter in collaboration with Ortho Biotech/J&J. This included as “black box” warning regarding using Aranesp (and other EPO products) to increase hemoglobin above 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy, with increased the risk for death and for serious cardiovascular events. Physicians are advised in the boxed warning and “Dosing and Administration” section to use the lowest dose of EPO products that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusions, and not to exceed 12 g/dL. Amgen noted that “The vast majority of oncologists and nephrologists do not appear to be maintaining Hb levels above 12 g/dL in approved indications:.”

In 2007, Aranesp and other EPO products are coming under increased criticism and scrutiny (see the Status section of the EPO Products entry, and the Trials section below), with trials suggesting that Aranesp and other EPO products are associated with higher mortality than previously thought, and may actually accelerate tumor growth and cancer progression, in addition to increasing concerns about cost-benefits and marketing practices.

In Dec. 2008, Dompe Biotec voluntarily withdrew its European Union license/approval for Nespo, citing " commercial reasons."

In Oct. 2009, 15 states joined in a federal lawsuit alleges that Amgen offered medical providers kickbacks to boost sales of Aranesp, leading to fraudulent claims for reimbursement from Medicaid and other insurers. Amgen sales representatives allegedly encouraged doctors and other healthcare providers to bill insurers for Aranesp that the practitioners received free from the company. The suit also alleges that Amgen, drug wholesaler ASD Healthcare and group drug-purchasing network International Nephrology (formerly ASD Healthcare and International Nephrology) offered "illegal inducements" to medical providers to increase sales of Aranesp, including sham consulting agreements, weekend retreats and other rewards.

In Jan. 2010, FDA announced it would review the safety of EPO products and Aranesp after studies showed "high amounts boost the risk of heart attacks, blood clots, and stroke."

In Oct. 2010, an FDA review committee voted 15-1 to maintain the approval of the three "blood-boosting medications from Amgen Inc." for "patients with chronic kidney disease who are not yet sick enough to receive dialysis." The panel said "patients with failing kidneys should continue taking" the anemia drugs, "despite a recent study showing they can increase the risk of stroke." The committee noted Aranesp shouldn't be withdrawn or limited to a 'rescue therapy' after a doubling of stroke risk was seen in a study of 4,000 patients with mild to moderate kidney disease. The panel recommended more studies to better explain which patients benefit from Aranesp and what dosing is ideal. In addition, the panel voted 9-5 against cutting dosing to patients with hemoglobin levels below 9 grams per deciliter of blood. The panel also voted "10-4 (with three members abstaining) to keep Aranesp as an option for patients with a history of stroke.

In Dec. 2012, Amgen has agreed to pay a settlement of $762 million to resolve federal litigation accusing the company of inappropriately marketing the anemia treatment, Aranesp, for unapproved uses. The company pleaded guilty to illegally introducing a misbranded drug into interstate commerce by promoting it in a way that was different from the dosages stated on the label. The plea was made on Dec. 18, 2012 in the US District Court for the Eastern District of New York and was accepted on Dec. 19, 2012 by the same Court. Amgen will pay approximately $612 million to resolve its civil liability for certain promotional practices of Aranesp (darbepoetin alfa), Epogen (epoetin alfa), Neupogen (filgrastim), Neulasta (pegfilgrastim), Enbrel (etanercept) and Sensipar (cinacalcet), as alleged in the unsealed qui tam complaints. Amgen will also pay $150 million to resolve its criminal liability relating to the misbranding of Aranesp.

In April 2013, Amgen has agreed to settle fedearal charges of illegally promoting its Aranesp by paying kickbacks to three long-term care pharmacy providers (Omnicare, PharMerica and Kindred Healthcare) in exchange for implementing ‘therapeutic programs’ that were designed to switch Medicare and Medicaid patients from a rival medicine. Amgen paid a fine of $24.9 million.

Tech. transfer: The product insert cites U.S. 5,618,698 and other patents/applications assigned to Amgen as covering the product. U.S. 5,618,698, “Production of erythropoietin,” April 8, 1997, expiring Apr 8, 2014, claims a variety of recombinant constructs and analogs of EPO manufactured in various expressions systems.

U.S. patent protection for Aranesp is projected by Decision Resources to expire in 2014 in most European countries.

Amgen was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Amgen and other companies are challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.

Trials: Clinical studies supporting approvals were performed with Aranesp containing Albumin (Human).

Aranesp is generally administered by subcutaneous or intravenous injection once per week (less frequently than with EPO), with some renal disease and other patients treated successfully with Aranesp administered once every two weeks. Aranesp should be administered once every two weeks in patients previously receiving epoetin alfa once per week. In contrast, EPO (e.g., Epogen, Procrit and Eprex) requires three injections per week for hemodialysis and pre-dialysis patients.

In Dec. 2005, Amgen issued a Dear Healthcare Provider” letter updating the label for Aranesp to make it clearer that PRCA cases have been reported in chronic renal failure patients receiving Aranesp and recommend that patients on hemodialysis patients receive the drug intravenously.

Disease: According to the American Heart Association, approximately 5 million Americans and over 4 million Europeans suffer from heart failure, for which Aranesp is currently in Phase III trials. Over 23 million suffer from heart failure worldwide. Heart failure is the leading cause of hospitalization for people over the age of 65 years and causes almost 1 million hospitalizations each year. This condition results in decreased oxygen delivery to the body due to a poorly functioning heart, while anemia reduces the oxygen content of the blood. When both heart failure and anemia occur together, oxygen delivery is further hampered. Although anemia is a common condition in heart failure patients, physicians caring have typically overlooked anemia in the absence of definitive studies suggesting that it should be treated.

In March 2008, the insert/labeling was modified by FDA to included an updated boxed warning for the class of drugs known as erythropoiesis-stimulating agents (ESAs), including Aranesp. The warning states that ESAs shortened overall survival and/or time-to-tumor progression in clinical studies in patients with breast, non-small cell lung, head and neck, lymphoid and cervical cancers, when dosed to target a hemoglobin of ≥12 g/dL. In the "Increased Mortality and/or Tumor Progression" warning section of the updated labeling, the interim results of the Preoperative Epirubicin Paclitaxel Aranesp (PREPARE) study in neo-adjuvant breast cancer were added as well as follow up data from the Gynecologic Oncology Group study in cervical cancer. Amgen addressed the science and safety of ESAs in oncology, including these new data, at an ODAC meeting the next week (March 13, 2008). Amgen informed healthcare professionals about the revisions to the U.S. prescribing information through a joint "Dear Healthcare Professional" letter with Ortho Biotech.

Trials: In the Dec. 2004 issue of Oncologist, results were published from an analysis of head-to-head trials that compared 200 µg Aranesp once every two weeks to 40,000 U Epogen once per week. This included data on 312 patients from three studies with breast, non-small cell lung cancer (NSCLC) or gynecological cancer. Patients in both groups achieved target hemoglobin of greater than or equal to 11 g/dL and had similar blood transfusion rates. Aranesp was shown comparable to Epogen, with increased convenience. The number and types of adverse events were similar between the two treatment groups and were consistent with those expected in these cancer patients.

Final results from a Phase III randomized open-label head-to-head study evaluating 200 g of Aranesp every two weeks vs. 40,000 U of Epoetin alfa (Procrit) once a week were published in the May 20, 2006, issue of the Journal of Clinical Oncology. Aranesp dosed every two weeks resulted in similar clinical efficacy as Epoetin alfa dosed once a week in boosting hemoglobin levels and reducing the need for red blood cell transfusions in cancer patients with chemotherapy-induced anemia. This was the largest randomized head-to-head comparison of Aranesp vs. Procrit. Comparability was reported in patient reported outcomes, including energy levels and impact on daily activities. Transfusions were similar in the two treatment groups (21% in the Aranesp group and 16%in the Epoetin alfa group), demonstrating non-inferiority of Aranesp and Epoetin alfa with respect to transfusion requirements. More than three-quarters of patients in both arms of the study achieved target hemoglobin of greater than or equal to 11 g/dL (80% in the Aranesp group and 86% in the Epoetin alfa group) and remained within the target during the study period (74% in the Aranesp group and 80% in the Epoetin alfa group). No differences were observed between treatment groups with respect to overall adverse events.

In Sept. 2005, Amgen initiated a Phase III randomized, placebo-controlled, double-blind, multicenter, multi-national trial to evaluate the effect of anemia treatment with Aranesp on morbidity and mortality in patients with heart failure. Numerous epidemiological studies have consistently shown that lower hemoglobin values (anemia), are associated with increased hospitalizations and mortality in heart failure. Positive results from pilot Phase II trials were reported in early 2006. Trials with Aranesp for cardiovascular indications: are further discussed below.

In Dec. 2005, interim results were reported from the first multi-center, randomized, double-blind, placebo-controlled, Phase III trial of Aranesp administered every three weeks in cancer patients with chemotherapy-induced anemia. Aranesp increased and maintained patient hemoglobin levels to the target level of greater than or equal to 11 g/dL and reduced the need for red blood cell transfusions by almost half compared to placebo. Among 386 patients (n=193 per arm) treated for up to 16 weeks,. 77% achieved target hemoglobin levels in the Aranesp-treated group vs. 55% in the placebo group. From week five to the end of treatment phase, the incidence of red blood cell transfusions was significantly lower for the Aranesp-treated group (24%) than for the placebo group (41%). Such a dosing schedule could allow physicians to treat anemia on the same schedule as chemotherapy, which is frequently administered every three weeks. This would reduce the number of patient visits patients and reduce costs. Also in Dec. 2005, promising interim results were reported from an ongoing Phase II of Aranesp (500 µg) for treatment of myelodysplastic syndrome.

In March 2006, results were reported from a 26-week, double-blind, placebo-controlled Phase II trial in 165 patients with symptomatic heart failure showing that Aranesp increased hemoglobin levels and improved symptoms, including patients’ symptoms scores using a questionnaire that measured ability to carry out tasks such as dressing themselves or climbing stairs, as well as heart failure-related symptoms such as swollen ankles and shortness of breath. The primary endpoint was the rate of hemoglobn rise per week during the titration period. Other endpoints included change from baseline to month six in six-minute walk distance, Patient’s Global Assessment (PGA), Minnesota Living With Heart Failure Questionnaire (MLHFQ), KCCQ and safety. Aranesp raised hemoglobin levels, significantly improved KCCQ total symptom score (Aranesp 8.2 vs. placebo 1.5; p = 0.027) and had a similar adverse event profile as previously seen in trials with Aranesp. Statistically nonsignificant improvements in PGA (Aranesp 65% vs. placebo 49%; p = 0.057), MLHFQ total score (Aranesp -10.1 vs. placebo -7.4; p = 0.413) and 6-minute walk distance (Aranesp 34.2 m vs. placebo 11.4 m; p = 0.074) were observed. Fixed dosing was as effective as weight-based dosing in raising Hb levels, and no change was observed in NYHA class (Aranesp -0.30 vs. placebo -0.23; p = 0.473). The number of adverse events was similar across treatment groups. There was also increasing evidence of a link, in general, between anemia and heart failure, and that treating anaemia in heart failure patients may be beneficial over time. This suggested that Aranesp may be useful for treatment of patients with heart problems, potentially opening a very large market. Anemia occurs in around 20-30% the 23 million patients affected by heart failure worldwide. Amgen subsequently initiated the Phase III RED-HF Trial (Reduction of Events with Darbepoetin alfa in Heart Failure), a randomized, double-blind, placebo-controlled, multicenter, multinational trial that will evaluate the effect of treatment of anemia with Aranesp on morbidity and mortality in patients with symptomatic heart failure.

In Jan. 2007, Amgen reported results from a randomized, placebo-controlled, Phase III trial with Aranesp for treatment of anemia directly associated with cancer (not due to chemotherapy toxicity). Patients in this study had not received chemotherapy or radiotherapy, and there were no plans for them to be given these. At 16 weeks, Aranesp was no more effective than placebo in reducing the number of transfusions needed or reducing fatigue. There were more deaths associated with Aranesp’s use than with the placebo. Amgen issues a letter to all oncologists warning them not to use Aranesp for cancer-related anemia.

In Feb. 2007, Amgen reported negative results from DAHANCA-10 trial of Aranesp in non-anemic head-and-neck cancer patients. The trial had enrolled 989 patients with hemoglobin less than 11 g/dL, and had been stopped in Oct. 2006, due to poorer locoregional control and survival in Aranesp-treated patients. The DAHANCA trial, along with four other ongoing trials, is testing Araesp`s efficacy in reducing tumor progression and promoting tumor death (i.e., not a reduction in anemia). No specific unexplained safety concerns were be identified.

In Feb. 2007, the Danish Head and Neck Cancer Group (DAHANCA) reported preliminary results from the first 484 patients in a study in over 522 patients designed to test whether Aranesp enhanced radiation therapy in patients with head and neck cancer (and off-label or unapproved indication). Aranesp-treated patients were actually 10% more likely to see their tumours grow, i.e,, Aranesp appeared to increase tumor growth/proliferation. Some simplistically interpreted the findings as showing that Aranesp causes cancer. The study was temporarily halted in Oct. 2006, with a decision not to resume the trial made on Dec. 1, 2006, due to Aranesp appeariing unlikely to improve the effect of radiation in non-anemic cancer patients. Amgen was informed of the findings in Dec. and promptly reported these to FDA. However, Amgen did not disclose the findings publicly until mid-Feb. 2007. The Amgen CEO later acknowledged in retrospect that the findings should have been revealed even though the company has not seen the raw data from the trial. The delayed public announcement could also make Amgen vulnerable to lawsuits from disgruntled investors.

In April 2007, Amgen reported reported results from a placebo-controlled study, “145 study,” of Aranesp in small-cell lung cancer patients showing no statistically significant increase in survival, the risk of death or PFS for Aranesp-treated patients compared to placebo. The trial enrolled 600 treatment-naïve patients with extensive-stage small-cell lung cancer (SCLC) receiving platinum-containing chemotherapy who were treated to an Hb target of 13 g/dL, higher than the approved labeling, which recommends against treating above 12 g/dL. Patients were randomized 1:1 to receive Aranesp 300 µg or placebo every week (QW) for the first four weeks, followed by once every three week (Q3W) dosing (commencing on week 5) for the remainder of the 24-week treatment period. Patients were treated to a target Hb of 13 g/dL, which is higher than indicated by the FDA-approved product label, with dose withholding at 14 g/dL. The study demonstrated no statistically significant difference in risk of death (overall survival Aranesp compared to placebo Hazard Ratio [HR]: 0.93, 95% CI: 0.78 to 1.11) or investigator determined progression-free survival (HR: 1.02, 95% CI: 0.86 to 1.21), i.e, Aranesp did not increase survival. There was a significant change in hemoglobin concentration from baseline in favor of Aranesp (a co-primary endpoint). Aranesp-treated patients also experienced a significantly lower risk of blood transfusions (HR: 0.40, 95% CI: 0.29 to 0.55). The overall safety profile, including thromboembolic events, was consistent with that described in the U.S. labeling. Like other studies, including Henke and DAHANCA, Study 145 was part of Amgen`s pharmacovigilence program testing Aranesp as a chemo-sensitizer in mostly non-anemic patients, an off-label indication that the medical community had mostly written off. These results were interpreted as neutral or positive, in the context of Aranesp and other EPO products coming under increasing criticism regarding safety issues, e.g., if Aranesp had a negative impact on survival in patients receiving chemotherapy, its sales would significantly suffer. Amgen noted, “These results contribute to the growing body of evidence on ESA safety, reinforcing the neutral impact of ESAs on survival in cancer patients suffering from chemotherapy-induced anemia.”

On April 17, 2007, Amgen reported the results from a randomized, double-blind, placebo-controlled Phase III study (“the 103 study”) evaluating the efficacy and safety of Aranesp for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy, i.e., patients who are anemic due to the cancer itself. Note, this is an off-label or unapproved indication in both the U.S. and EU. As had been reported in Jan., the study did not meet its primary endpoint of reducing red blood cell (RBC) transfusions in the Aranesp treatment group. Transfusion occurrences from weeks 5 to 17 favored Aranesp, but were not statistically significant between the groups (hazard ratio: 0.85, p=0.32). Among those receiving Aranesp, after two years there was a significantly higher proportion of patients with a hemoglobin response (p <0.0001), hemoglobin correction (p <0.001), and hematopoietic response (p=0.002) compared with placebo. The adverse event rate was similar between the groups. However, the overall number of deaths was greater in the Aranesp group (48.5% versus 46% in placebo; hazard ratio: 1.29; p=0.006). The mean (SD) number of days between prior chemotherapy and first study drug dose was 262 (572) days for the Aranesp group compared to 315 (660) for the placebo arm. Aranesp also failed to to reach the trial’s endpoints of reducing blood transfusions. In post-hoc analyses adjusting for stratification factors at randomization and sex, stage IV disease, prior chemotherapy use and prior radiotherapy use, there remained a significant difference in survival between the groups. However, hazard ratios and statistical significance diminished when the analyses were further adjusted for known prognostic factors including baseline ECOG status, tumor type, tumor stage, baseline FACT-F cutoff at median and baseline Hb (hazard ratio: 1.17, p=0.11). The principal investigator noted, “Since this [study] was not designed as a survival study and statistical significance diminished when the analyses were adjusted for known prognostic factors, there is no clear explanation for the increase of deaths in the Aranesp group.” Amgen acknowledeged that the study had found “a statistically significant increased risk of death.” These were among the findings discussed by the the oncology drug advisory committee at its meeting on May 10, 2007 (see the Status section of the EPO Products entry above, #132)

Amgen is currently conducting trials to expand indications: for Aranesp. The Phase III TREAT study is underway in ~ 4,000 diabetic patients with chronic kidney disease and anemia not requiring dialysis. The Red-HF study is testing whether Aranesp reduces risk of death and complications in 3,400 anemic heart-failure patients

In Oct. 2009, results were published the results from TREAT (the Trial to Reduce Cardiovascular Events with Aranesp Therapy), a randomised, double-blind and placebo-controlled, Phase III pivotal study of patients with chronic kidney disease (CKD) not on dialysis, moderate anemia and type-2 diabetes. The study failed to meet its primary objectives of a reduction in all-cause mortality, cardiovascular morbidity, including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia, or end-stage renal disease (ESRD). The study of "4,038 people with type 2 diabetes, kidney problems, and moderate anemia" also found that strokes "occurred in 101 patients given Aranesp and 53 patients given" a placebo. The primary endpoints were a composite of time to all-cause mortality or cardiovascular morbidity (including heart failure, heart attack, stroke, or hospitalization for myocardial ischemia) and a composite of time to all-cause mortality or ESRD. Among the components of the primary cardiovascular composite endpoint, the risk of stroke increased by almost two-fold in patients in the Aranesp arm. Although stroke is a recognized risk with erythropoiesis-stimulating agent (ESA) therapy, and has been identified in warnings in US labeling since 2001, the risk observed in TREAT was of higher magnitude than that seen in previous clinical trials in CKD patients not on dialysis. A post hoc analysis indicated that there were no significant differences between treatment arms in the incidence of cancer or of all-cause deaths in patients who developed cancer during the trial. Among patients with a history of cancer, 60 of 188 patients taking Aranesp died, compared with 37 of 160 on placebo. However, this analysis also showed an excess in overall mortality among patients in the Aranesp arm with a history of cancer. As the first, large-scale placebo-controlled study to examine the use of anemia therapy in diabetic CKD patients not on dialysis, the results of the study demonstrated that in many diabetic CKD patients not on dialysis with moderate anemia, the risk of treatment to a target hemoglobin level of 13 g/dL will exceed the benefit of reducing the need for transfusions. For many, the bottom line appeared to be that Aranesp (and perhaps by extension Procrit/Epogen) probably is "Miracle-Gro for Cancer," as alleged by American Cancer Society president Otis Brawley.

Market: Aranesp is the main competitor with Procrit from Ortho/J&J for their approved cancer chemotherapy-related indications:. With the approval of Aranesp for these non-renal disease-related indications:, Amgen finally had an EPO product to compete with Procrit from Ortho/J&J in this major U.S. market. Aranesp also competes against Amgen’s own Epogen for market share in the renal disease/dialysis market, and against Procrit (in the U.S., where used off label for this indication) and Eprex (outside U.S.), both from Ortho/J&J, for non-renal disease/dialysis indications:. However, with many kidney failure patients receiving dialysis treatment several times weekly, the less frequent dosing with Aranesp is less of a factor than for cancer chemotherapy-related use, and Aranesp’s capturing of market share from well-established Epogen depends largely on the costs of Epogen and Procrit in the U.S. and Eprex internationally.

Total worldwide sales of Aranesp were $2.997 billion in 2011; $2.995 billion in 2010; $3.09 billion in 2009; $3.334 billion in 2008; $4.04 billion in 2007; $4.15 billion in 2006; $3.273 billion in fiscal 2005; $2.473 billion in 2004; about $1.5 billion in 2003 (acheiving blockbuster status); $416 million in 2002; and $42 million in 2001 (with Aranesp approved in Sept.). Upon approval, Aranesp quickly captured substantial U.S. market share previously held by Epogen and Procrit. Sales for dialysis indicaions are now relatively steady, but have decreased recently, with various safety issues attributed to Aranesp and other EPO products.

In 2012, total sales by Amgen were $489 million, including $187 million in the U.S. In 2008, total Aranesp sales by Amgen were $3,137 million in 2008 versus $3,614 million in 2007, a 13% decrease. This decrease in sales was primarily due to a decline in demand reflecting reaction to regulatory and reimbursement developments and, to a lesser extent, loss of market share.

In 2007 and 2008, Amgen reported that about 60% of Aranesp sales were for cancer indications:. In 2006, Amgen reported that 16% of cancer patients initiating therapy at an hemoglobin (Hb) levels above 11 g/d, the cut-off point for most insurance reimbursement.

Worldwide Aranesp sales by Amgen were $4.15 billion in 2006, about 29% of the company’s total revenue. Total U.S. sales of $2.8 billion included about $700 million for non-cancer indications: (dialysis); and $2.1 billion for cancer indications:, including $500 million for anemia of cancer, $200 million for myelodysplastic syndromes and $1.4 billion for chemothrapy-induced anemia. Ex-U.S. sales of $1.37 billion included $800 million for non-cancer indications:; and $580 for cancer indications:, including $60 million for anemia of cancer, $10 million for myelodysplastic syndromes and $500 billion for chemothrapy-induced anemia.

In March. 2007, Friedman, Billings, Ramsey & Co. (FBR) estimated Aranesp worldwide revenue for Amgen of $4.121 billion in 2006, $4.030 billion in 2007, $4.861 billion in 2008, $3.523 billion in 2009, $3.419 billion in 2010, $3.327 billion in 2011, and $3,341 billion in 2012. Only week previously, before some of the safety concerns with EPO products were reported and products were relabeled with new warnings, FBR had projected much higher sales, e.g,. $4.190 billion in 2010, $4.211 billion in 2011, and $4.232 billion in 2012. U.S. sales are projected to be $2.790 billion in 2006, $2.567 billion in 2007, $2.413 billion in 2008, $2.265 billion in 2008, $2.365 billion in 2009, $2.376 billion in 2010, $2.388 billion in 2011, and $2.412 billion in 2012.

The early 2007 negative results from several Aranesp cancer trials (see Trials section above) are not expected to significantly affect Aranesp sales, since both indications: tested are off-label and the EPO levels in the DAHANCA trial were way above the normal target range in anemic patients. Many expect oncologists to continue use of Aransesp for anemia associated with cancer in ≤10% of their Aranesp-treated patients. Four other trials testing Aranesp use with other tumor types are ongoing (in early 2007), with results from Amgen-sponsored Study-145 expected later in 2007. The recent trial failures may revive assertions that EPO receptors on tumors can be activated by high EPO doses and stimulate tumor growth.

In Oct. 2005, Ortho/J&J reported in a court brief charging Amgen with monopolistic sales practices related to Aranesp (see below) that Aranesp then held an ~66% of U.S. erythropoiesis (EPO-related) agent sales to cancer clinics, while the U.S. market share in oncology clinics for Procrit fell to 34% from 55% in the first quarter of 2004

In Jan. 2011, Amgen raised the price of Aranesp by 4.4% to offset falling revenue, which was expected to decline further due to new Medicare bundling payment rules for dialysis services.

The 2007 Average Wholesale Prices (AWPs) for a sampling of the large number of presentations in which Aranesp is packaged include $137.28/1 mL, 0.025 mg Albumin-preserved vial, $549.12 for four; $219.66/1 mL, 0.040 mg Albumin-preserved vial, $878.64 for four;$549.12/1 mL, 0.1 mg Albumin-preserved vial, $2,196.48 for four; $823.68/1 mL, 0.15 mg/0.75 mL Albumin-free vial, $3.294.72 for four; $1,98.24/0.4 mL, 0.2 mg/0.04 mL Albumin-free prefilled syringe; and $2,7450.60/1 mL, 0.5 mg/1 mL Albumin-free prefilled Singleject syringe. For comparison the 2005 Average AWP for Albumin-preserved Aranesp were $137.28/1 ml, 0.025 mg/mL Singleject syringe ($124.69 in 2004), $512.64 ($498.76 in 2004) for a package of 4; $205.08/1 mL Singleject, 0.04 ml/mL vial ($199.50 in 2004), $820.32 for 4 ($798.00 in 2004); $$128.16/0.42 mL, 0.025 mg/mL vial ($119.70 in 2004), $512.64 for 4 ($478.80 in 2004); $$307.56/1 mL, 0.06 mg/mL Singleject ($299.25 in 2004); $205.08/0.4 mL, 0.04 mg/0.4 mL vial ($191.52 in 2004); and $512.68/0.5 mL, 0.1 mg/mL vial ($498.75 in 2004). For Albumin-free Aranesp, the AWP is $512.64/1 mL, 0.1 mg/mL vial ($498.75 in 2004); $307.56/0.3 mL, 0.06 mg/mL vial ($299.25 in 2004); $1,025.28/1 mL, 0.2 mg/mL prefilled syringe ($997.50 in 2004); $1,537.92/1 mL, 0.3 mg/mL prefilled syringe ($1,496,25 in 2004); $1,537.92/0.6 mL, 0.3 mg/mL Singleject ($1,537.92 in 2004); and $2,563.20/1.0 mL, 0.5 mg/mL single-dose vial ($2,394.00 in 2004) (Red Book, 2007).

In May 2004, Aranesp’s list price was reported as $499 (per treatment) for dialysis indications:. Typical pre-dialysis treatment was reported to cost $126/week (equiv. to $6,552/year; presuming 0.45 µg/kg weekly) and; typical chemotherapy-related use about $628/week (equiv. to $18,252/year; presuming 2.25 µg/kg weekly). Based on use (taking dosage and dosing frequency into account), Aranesp costs ≤10% more than conventional EPO (e.g., Epogen). For many patients, this slight increase in cost may be more than compensated for by the need for less frequent dosing and associated decrease in medical costs and increased convenience.

The Center for Medicare and Medicaid Services (CMS) currently has set a Medicare/Medicaid reimbursement rate for physician in-office use of Aranesp at 95% the Average Wholesale Price (AWP). This accounts for the great majority of Aransep sales. In 2005, CMS change to basing reimbursement on Average Sales Price (ASP) plus 6%. This did not significantly change the reimbursement price for Aranesp.

Effective Jan. 1, 2003, Aranesp was being reimbursed by CMS for chemotherapy-related anemia (in-hospital use) at about 48% the AWP under the CMS Hospital Outpatient Prospective Payment System, i.e. for hospital outpatient use, which accounts for up to 15% of total Aranesp sales. CMS has specifically approved Aranesp reimbursement for dialysis-related indications:. CMS concluded that Aranesp and conventional EPO were “functionally equivalent,” with each product achieving the same efficacy for treatment of anemia, even though the products are far from equivalent in terms of identity, potency, bioequivalence, etc., and ignoring the roughly comparable costs when dosage and dose frequency are considered. By comparison, J&J’s Procrit is reimbursed at 68.2% of AWP. CMS reimbursement schedules are often used in other settings, with CMS reimbursement rates affecting other institutions acceptance and use of products. Many view the CMS ruling as primarily an effort to put pressure on Amgen to lower Aranesp prices. In Nov. 2002, Amgen filed suit against the CMS and its parent, DHHS, seeking an injunction that would prohibit the reduction in the reimbursement rate for Aranesp. On Dec. 24, 2002, a U.S. District Court dismissed the complaint, citing Amgen as lacking standing to challenge the CMS. Amgen is appealing.

In July 2004, CMS released a draft of its new policy for Aranesp reimbursement for anemia related to end-stage renal disease, with the policy slated to go into effect in 2005. The reimbursable hematocrit level for EPO, including Aranesp, would be expanded to 39% from 37.5%, allowing more patients to qualify; and reimbursement, starting in 2005, would be decreased by 15% from 2004 levels (reducing reimbursement from 95% of AWP to 85% of AWP). CMS is expected to shift to reimbursement based on Average Selling Price (ASP) + 6% in 2005. This is not expected to significantly affect sales of Aranesp, which has been gaining market share among EPO products, with an increase of 46% in sales over the past 18 months.

In Oct. 2005, Ortho Biotech/Johnson & Johnson (J&J) filed an antitrust lawsuit in federal court alleging that Amgen of engaging in anticompetitive bundling sales practices to monopolize the market for sales of anti-anemia therapeutics to oncology clinics. As discussed in the other Amgen and Orhto/J&J EPO-related entries, the two companies have long been battling each other in the marketplace and in federal courts over alleged restrain-of-trade practices, off label sales and other marketing issues. Amgen allegedly implemented an anticompetitive “tying” arrangement and pricing scheme requiring cancer clinics to purchase Aranesp rather than Ortho’s Procrit (epoetin alpha). Under Amgen’s pricing scheme, clinics purchasing large amounts of Aranesp receive substantial discounts on purchases of the company’s white blood cell growth factors, Neulasta (pegfilgrastim) and Neupogen (filgrastim), which currently hold 98% of the market for this class of products (no other competition). Ortho alleged that Amgen’s pricing scheme became even more “coercive” on Oct. 1, with failure to buy at least 75% of erythropoiesis therapeutics from Amgen forcing the prices of Neulasta and Neupogen above those reimbursed by Medicare/Medicaid. For a clinic to continue to receive the same level of rebates it had been receiving it had to increase its Aranesp share up to 90%. Ortho alleges that Amgen’s tactics had been extremely successful in increasing sales of Aranesp, with Aranesp rapidly gaining U.S. market share (see discussion above) at the expense of Procrit.

In March 2008, Amgen and Ortho/J&J settled the long-running legal dispute filed by J&J over Amgen's bundling of Aranesp with its Neupogen and Neulasta franchises. Amgen lost and paid $200 million to resolve antitrust claims. Despite this settlement, it is possible that Amgen, on balance, came out ahead (made a profit) from its illegal promotional activities.

In Feb. 2009, it was reported that an "unidentified whistleblower" had filed a lawsuit against Amgen Inc. accusing the company of illegal marketing of its blockbuster drugs Enbrel and Aranesp. An amended version of the lawsuit had been filed in 2007 in the U.S. District Court for the District of Massachusetts in Boston, but had been under seal in accordance with a federal whistleblower law that protects the identify of the plaintiff. Wyeth (WYE), which co-markets Enbrel with Amgen, also was named as a defendant, along with wholesale drug distributor AmerisourceBergen Corp. (ABC), online health-information provider WebMD Health Corp. (WBMD) and other defendants.

In Dec. 2012, Amgen pleaded guilty to a misdemeanor misbranding charge for mismarketing iAranesp. The plea was part of a deal that included $150 million in criminal penalties--and a total payment of $762 million. At $762 million, Amgen's marketing settlement would rank among the biggest in the industry in recent years. Amgen reported that it had set aside $780 million to resolve government investigations and whistleblower suits. The guilty plea involved Amgen's promotion of Aranesp for anemia caused by cancer, an indication not approved by the FDA. Rather, it is approved to treat anemia caused by chemotherapy. The company was also accused of touting higher doses and different treatment schedules from those the FDA-approved label stipulated.

Competition: In Dec. 2008, Merck announced its intension to develop and market biosimilars/follow-on biologics, with its first target being an improved version of Aranesp. Merck had acquired GlycoFi, including its proprietary technology for yeast glycosylation, and will be applying this technology to its Aranesp follow-on. Merck projects launch in 2012.

In Aug. 2010, Dr Reddy’s Laboratories launched Cresp, "the first generic (biosimilar or biogeneric) darbepoetin," in India. Dr Reddy’s expected Cresp to deliver patients savings of up to 28% if they switch from generic epoetin alfa, up to 55% when switching from innovator epoetin alfa (Eprex, Johnson & Johnson) and up to 85% if they switch from innovator darbepoetin alfa (Aranesp, Amgen) to Cresp. In India, Eprex costs Rs10,000 for a month’s treatment. Cresp costs Rs4,500.

Avesthagen (India) is developing a darbopoeitin biosimilar (AVDESP), with trials starting in India in Aug. 2009.