Hetero launches darbepoetin alfa biosimilar in India

The Hetero Group, one of the largest manufacturers and suppliers of activepharmaceutical ingredients to the Indian pharmaceutical industry, yesterdayannounced the launch of its first biosimilar product in India, darbepoetin alfa.

This launch marks a significant advancement for Hetero in a biosimilars market expected to grow to US$ 24B in the next five years. In partnership with several prominent pharmaceutical companies, Hetero is launching the drug across India.

http://www.biosimilarnews.com/hetero-launches-darbepoetin-alfa-biosimilar-in-india  june 19 2014

Darbepoetin alfa (rINN) /dɑrbəˈpɔɪtɨn/ is a synthetic form of erythropoietin. It stimulates erythropoiesis (increases red blood celllevels) and is used to treat anemia, commonly associated with chronic renal failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.

The drug was approved in September 2001 by the Food and Drug Administration for treatment of anemia in patients with chronic renal failure by intravenous or subcutaneous injection.^[1] In June 2001, it had been approved by the European Medicines Agency for this indication as well as the treatment of anemia in cancer patients undergoing chemotherapy.^[2]

Dr. Reddy’s Laboratories launched darbepoetin alfa in India under the brand name ‘Cresp’ in August 2010. This is the world’s first generic darbepoetin alfa. Cresp has been approved in India.

Human erythropoietin with 2 aa substitutions to enhance glycosylation (5 N-linked chains), 165 residues (MW=37 kD). Produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

APPRLICDSRVLERYLLEAKEAENITTGCAEHCSLNENITVPDTKVNFYAWKRMEVGQQA
VEVWQGLALLSEAVLRGQALLVNSSQPWEPLQLHVDKAVSGLRSLTTLLRALGAQKEAIS
PPDAASAAPLRTITADTFRKLFRVYSNFLRGKLKLYTGEACRTGDR

Darbepoetin is produced by recombinant DNA technology in modified Chinese hamster ovary cells.^{[citation needed]} It differs from endogenous erythropoietin (EPO) by containing two more N-linked oligosaccharide chains. It is an erythropoiesis-stimulating 165-amino acid protein.

Like EPO, its use increases the risk of cardiovascular problems, including cardiac arrest, arrhythmia, hypertension and hypertensive encephalopathy, congestive heart failure, vascular thrombosis or ischemia, myocardial infarction, edema, and stroke. It can also increase risk of seizures. A recent study has extended these findings to treatment of patients exhibiting cancer-related anemia (distinct from anemia resulting from chemotherapy).^[3] Pre-existing untreated hypertension is a contra-indication for darbepoetin, as well as some hematologic diseases. Other reported adverse reactions include hypotension, fever, chest pains, nausea and myalgia.

Like EPO, it has the potential to be abused by athletes seeking a competitive advantage. Its use during the 2002 Winter Olympic Games to improve performance led to the disqualification of cross-country skiers Larisa Lazutina and Olga Danilova of Russia and Johann Mühlegg of Spain from their final races.

Safety advisories in anemic cancer patients

Amgen sent a “dear doctor” letter in January, 2007, that highlighted results from a recent anemia of cancer trial, and warned doctors to consider use in that off-label indication with caution.

Amgen advised the U.S. Food and Drug Administration (FDA) as to the results of the DAHANCA 10 clinical trial. The DAHANCA 10 data monitoring committee found that 3-year loco-regional control in subjects treated with Aranesp was significantly worse than for those not receiving Aranesp (p=0.01).

In response to these advisories, the FDA released a Public Health Advisory^[4] on March 9, 2007, and a clinical alert^[5] for doctors on February 16, 2007, about the use of erythropoeisis-stimulating agents such as epogen and darbepoetin. The advisory recommended caution in using these agents in cancer patients receiving chemotherapy or off chemotherapy, and indicated a lack of clinical evidence to support improvements in quality of life or transfusion requirements in these settings.

In addition, on March 9, 2007, drug manufacturers agreed to new “black box” warnings about the safety of these drugs. On November 8, 2007, additional “black box” warnings were included on the aranesp label, at the request of the FDA.

On March 22, 2007, a congressional inquiry into the safety of erythropoeitic growth factors was reported in the news media. Manufacturers were asked to suspend drug rebate programs for physicians and to also suspend marketing the drugs to patients.

Business considerations for drug manufacturers

Epogen and Darbepoetin alfa had more than $6 billion in combined sales in 2006. Procrit sales were about $3.2 billion in 2006.

Darbepoetin alfa

Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a604022
Licence data	EMA:Link, US FDA:link
Pregnancy cat.	B3 (AU)
Legal status	Prescription Only (S4) (AU)
Identifiers
CAS number	11096-26-7
ATC code	B03XA02
DrugBank	DB00012
Chemical data
Formula	C815H1317N233O241S5
Mol. mass	18396.1 g/mol

Aranesp (darbepoetin alfa) is an erythropoiesis-stimulating protein that is produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Aranesp is a 165-amino acid protein that differs fromrecombinant human erythropoietin in containing 5 N-linked oligosaccharide chains, whereas recombinant human erythropoietin contains 3 chains. The 2 additional N-glycosylation sites result from amino acid substitutions in the erythropoietin peptide backbone. The approximate molecular weight of darbepoetin alfa is 37,000 daltons.

Aranesp is formulated as a sterile, colorless, preservative-free solution containing polysorbate for intravenous or subcutaneous administration. Each 1 mL contains polysorbate 80 (0.05 mg), sodium chloride (8.18 mg), sodium phosphate dibasic anhydrous (0.66 mg), and sodium phosphate monobasic monohydrate (2.12 mg) in Water for Injection, USP (pH 6.2 ± 0.2).

References

1.  Jay P. Siegel (2001-09-17). “Product Approval Information – Licensing Action”. United States Food and Drug Administration. Archived from the original on 2006-10-22. Retrieved 2007-01-27.
2.  “European Public Assessment Report (Abstract)” (PDF). European Medicines Agency. 2001-06-08. Retrieved 2007-01-27.
3.  Pollack, Andrew (2007-01-26). “Amgen Finds Anemia Drug Holds Risks in Cancer Use”. The New York Times. Retrieved 2007-01-27.
4. “FDA Public Health Advisory: Erythropoiesis-Stimulating Agents (ESAs): Epoetin alfa (marketed as Procrit, Epogen), Darbepoetin alfa (marketed as Aranesp)”. Archived from the original on 2007-05-28. Retrieved 2007-06-05.
5.  “Information for Healthcare Professionals: Erythropoiesis Stimulating Agents (ESA)”. Archived from the original on 2007-05-15. Retrieved 2007-06-05.