Status – marketed in U.S. and Europe

Organizations involved:

Abraxis BioScience, LLC – Manuf.; R&D; Tech.; World mark.

AstraZeneca plc – USA mark.

American BioScience, Inc. – R&D; Tech.; Former

American Pharmaceutical Partners, Inc (APP) – R&D; Tech.; Former

Cross ref.: See the Albumin entry. [Note, as somewhat of a borderline biopharmaceutical, with albumin used as a carrier for an anticancer drug, this monograph does go into as much depth as for mainstream biopharmaceuticals].

Description: Abraxane is a lyophilized (freeze-dried) formulation of paclitaxel, a cancer chemotherapy taxane-family drug, bound to 130 nm Albumin particles (using nab technology) to improve delivery and pharmacokinetics. Albumin is the carrier for paclitaxel. The nab technology used binds water-insoluble compounds (paclitaxel) with albumin in a nanoparticle form, which makes the product readily bioavailable after administration. Prior paclitaxel drugs used solvents to faclitate delivery. Nanoparticles composed of human albumin with paclitaxel molecules bound to the surface, are capable of boosting the amount of paclitaxel available to kill malignant cells.

Abraxane is supplied as a lyophilized powder for reconstitution with 20 mL of 0.9% Sodium Chloride Injection, USP prior to intravenous infusion. Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human albumin. Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel. Abraxane is free of solvents. Vials are stored at room temperature.

Paclitaxel belongs to a class of chemotherapy drugs called taxanes, including the drugs Taxol (containing paclitaxel) and Taxotere (containing docetaxel). The chemical name for paclitaxel is 5,20-Epoxy-1,2,4,7,10,13-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Although taxanes are obtained from the bark of Taxus media trees, they are small molecule drugs derived from non-living tissue, with no manufacture or processing by living organisms, and are not considered biopharmaceuticals. Taxanes can stop cancer cells from repairing themselves and from making new cells. Studies have shown them to be effective in treating women with advanced breast cancer that does not respond to other forms of chemotherapy. Both taxanes are approved by the FDA for women with early-stage disease.

Prior taxane drugs have contained detergents and cremophor, a derivative of castor oil, as a solvent, with these causing adverse effects generally requiring treatment with corticosteroids and antihistamines.

Abraxane contains albumin (human) derived from human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for Albumin..

Biological.: is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in theinhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis

Other approved paclitaxel preparations, such as Taxol, use various detergents/solvents to help the paclitaxel molecule dissolve in water. Solubility in water is essential for administering drugs into the bloodstream. But the detergents used in other paclitaxel formulations can themselves be toxic, requiring that patients receive additional medications, such as corticosteroids, to counteract those toxicities and avoid hypersensitivity reactions. Albumin nanoparticles overcome this solubility issue, taking advantage of the fact that albumin is the body’s natural carrier of molecules that are poorly soluble in water.

The improved efficacy of Abraxane over Taxol was at first suspected to result simply from the fact that patients could be given larger doses of paclitaxel, due to the lack of detergents in the nanoparticulate formulation. But subsequent studies found that albumin interacts with two different proteins that actively transport albumin – and the paclitaxel molecules associated with it – into tumors. The first protein, gp60, is found on the surface of the endothelial cells that line the interior of blood vessels. This protein binds to albumin, starting a series of biochemical events that results in albumin and the associated paclitaxel, being transported out of the bloodstream, through the endothelial cell and out into the fluid surrounding tumor cells. As a result, paclitaxel is removed from the bloodstream and becomes concentrated in the vicinity of malignant cells. The detergents used in other paclitaxel formulations cannot take advantage of this transport mechanism. The second protein, Secreted Protein, Acidic and Rich in Cysteine (SPARC), is found on the surface of many types of tumor cells, and its presence is associated with a poor prognosis. SPARC also binds to albumin. However, the albumin and paclitaxel bound to it remain in the tumor cells. The result is that more paclitaxel ends up in tumor cells. Patients with SPARC-positive tumors, that is, those with the worst prognosis, generally respond more favorably to Abraxane therapy.

Companies.: Abraxane was jointly developed by American Pharmaceutical Partners, Inc (APP) and American BioScience, Inc (ABI). Their biotechnology business was spun-off to operate as Abraxis BioScience in 2007. Abraxane is manufactured and marketed by Abraxis BioScience LLC. It is co-marketed in the U.S. by AstraZeneca.

In April 2006, AstraZeneca received U.S. comarketing rights for an initial 5.5 year term, beginning on July 1, 2006. AstraZeneca dedicates sales representatives to support Abraxane and also funds half of the costs for promotional and advertising programs. Further milestone payments are made to Abraxis upon the achievement of new indication approvals within pre-specified timelines. AstraZeneca receives a commission of 22% of Abraxane net sales within the U.S. during this term, with a trailing commission of 10% and 5% for the two years following the end of this period. A braxis also granted AstraZeneca right of first refusal to license or co-promote Abraxis outside the U.S., other than selected countries, should a partner be sought. AstraZeneca further agreed to sell its range of U.S. branded anaesthetics and analgesic products to Abraxis BioScience.

FDA class: NDA drug

Approvals: Date = 20050107; NDA, as a 505(b)(2) generic drug approval (comparable to Taxol)

Indications: [Full text of the INDICATION section of the product insert/labeling]:

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

Status: In Feb. 2001, American BioScience obtained agreement that the FDA division of Oncology Drug Products would accept the NDA application as a 505(b)(2) generic drug application.

On Jan. 23, 2008, Abraxis received approval for Abraxane in the European Union (EU). At that time, Abraxane was approved in 33 countries including the U.S. and Canada. In Dec. 2008, Abraxis launched Abraxane in the EU, starting in the U.K.

Tech. transfer: Relevant U.S. patents include 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; and 6,753,006.

Trials: Clinical trials have shown Abraxane to be safer than Taxol, as well as more effective, in treating patients with breast cancer who had failed earlier therapies.

Trials have shown that Abraxane is also effective at treating non-small cell lung cancer and metastatic melanoma. Based on these data, Abraxix hopes to receive FDA approval to treat these types of cancer, in addition to the approval for breast cancer.

The trials supporting FDA approval included two single arm studies enrolling a total of 106 patients and one multicenter randomized trial. The multicenter trial was conducted in 460 patients with metastatic breast cancer who were randomized to receive either nanoparticle paclitaxel 260 mg/m2 administered as a 30-minute infusion or paclitaxel 175 mg/m2 given over three hours. Fifty-nine percent of patients had received one or more prior chemotherapy regimens, and 77% had received an anthracycline-containing regimen. T he objective response rate verified by central review was 21.5% (95% CI: 16.2 percent to 26.7%) for nanoparticle paclitaxel compared to 11.1% (95% CI: 6.9% to 15.1%) for paclitaxel (p=0.003).

Medical: Abraxane is used for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline, unless clinically contraindicated. Neutropenia is a side effect of paclitaxel, and patients must be monitored for this.

The recommended regimen for Abraxane is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Since Abraxane does not require taking pre-medication, e.g., corticosteroids, to reduce the risk of an allergic reaction, an Abraxane treatment averages 30 minutes compared with three hours for Taxol.

Market: In 2005, Abraxis BioScience recorded $134 million sales in the U.S. in its first year of launch.