Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications
While first-generation nanodrugs reduced toxicity, next-gen treatments are being designed to increase efficacy.
Second-generation nanotherapeutics to treat cancer have drawn attention and funding as companies move to improve the efficacy of these treatments and expand their applications. Generally in the size range of 1–100 nm, these drugs have emerged as novel antitumor agents because they have the potential to deliver high concentrations of drugs to cancer cells and cause less toxicity than systemically administered drugs.
The currently approved and marketed cancer nanodrugs consist of chemotherapeutic agents formulated with liposomes or bound to the protein albumin. The first nanodrug sanctioned by the FDA for breast cancer was Abraxis BioScience’s Abraxane, in 2005, for the treatment of metastatic disease. It was made possible by the firm’s nanoparticle albumin-bound (nab) technology.
The other approved nanodrug is pegylated liposomal doxorubicin, which is marketed as Doxil in the U.S. by Centocor Ortho Biotech and in Israel by Janssen-Cilag for ovarian cancer that has progressed or recurred after platinum-based chemotherapy. Schering-Plough has exclusive rights to the medication, branded as Caelyx, in the rest of the world, excluding Japan, for the same indication as well as AIDS-related Kaposi’s sarcoma. A significant justification for approving Doxil/Caelyx had been the reduction of associated, significant toxicities including cardiomyopathy, bone marrow depression, alopecia, and nausea rather than the enhancement of clinical efficacy.
Sopherion Therapeutics has developed a nonpegylated form of the drug, called Myocet, and is now trying to expand into the first-line setting for Her2-positive metastatic breast cancer. In January it received Fast Track Designation from the FDA for this indication. A Phase III comparison of free doxorubicin vs. Myocet, used in combination with cyclophosphamide, to treat advanced breast cancer showed that the incidence of cardiac events was 29% vs. 13% and of congestive heart failure was 8% vs. 2% for the doxorubicin group and the Myocet group, respectively. Both groups, however, achieved comparable response rates of about 26% and progression-free survival times of about four months.
Drug developers are thus attempting to further enhance the value of anticancer nanodrugs beyond reduced toxicity. The aim is to create second-generation nanotherapeutics that have greater specificity, target selectivity, and an improved therapeutic index. For example, preclinical studies have shown that doxorubicin-loaded liposomes conjugated with folic acid can be internalized upon binding with folate receptors on cancer cells. This suggests the potential for improved targeting and a subsequent internalization strategy in the treatment of several multidrug-resistant tumors. And doxorubicin-loaded long-circulating liposomes modified with RGD-peptide motif can reportedly target the neovasculature of angiogenic tumors.
Abraxis is also trying to fine-tune its nanodrug product. Abraxane consists of an albumin-bound form of paclitaxel with a mean particle size of approximately 130 nm. It is free of toxic solvents and showed a superior response rate with an almost doubling of the reconciled target lesion response rate when compared with the solvent-based Taxol (paclitaxel injection) in a prospectively randomized trial of 460 patients with metastatic breast cancer, the company reports. Because it contains no toxic solvents, the product allowed the administration of 50% more chemotherapy with a well-tolerated safety profile, the firm notes.
On June 30, Celgene acquired Abraxis for $2.9 billion in cash and stock. Celgene’s own cancer products had generated revenues of close to $2.7 billion in 2009, mostly from its multiple myeloma drug Revlimid. The transaction thus gives Celgene commercial operations in the solid tumor market. The firm believes that it could add $1 billion to its annual sales by 2015. Abraxane brought in about $315 million in sales last year, 88% of Abraxis’ revenue.
Abraxis is seeking to expand Abraxane’s use into lung and pancreatic cancers. Earlier in June, Abraxis and Specialised Therapeutics Australia reported positive Phase III results in advanced non-small-cell lung cancer (NSCLC) when compared with Taxol in the first-line setting. The study was conducted at 102 sites globally and enrolled 1,052 patients. It showed that patients treated with Abraxane and carboplatin demonstrated a significant improvement in overall tumor response rate compared with patients treated with Taxol and carboplatin.
Should the FDA approve Abraxane for treatment of NSCLC, Celgene will have to pay Abraxis $250 million. The company will be further obliged to pay $300 million if the drug gains FDA approval for treating pancreatic cancer and yet another $100 million if this cancer sanction comes by April 1, 2013.
Abraxis says that the delivery specificity occurs through targeting a tumor-activated, albumin-specific biologic pathway with the albumin nanoshell. This nanoshuttle system then activates an albumin-specific (Gp60) receptor-mediated transcytosis path through proliferating tumor cell walls. Once in the stromal microenvironment, the albumin-bound drug may be preferentially localized by a second albumin-specific binding protein, SPARC, which is secreted into the stroma by tumor cells. The resulting collapse of stroma surrounding the tumor cell may thus enhance the delivery of the nab-chemotherapeutic to the intracellular core of the tumor cell itself.
Another firm in the nanodrug development space is Bind Biosciences. On June 29, it announced raising $12.4 million in a Series C-1 financing. The proceeds will be used to conduct initial clinical trials on its lead candidate, BIND-014, expected to start later this year in patients with taxane-sensitive tumors such as prostate, breast, and lung cancers.
Bind CEO, Scott Minick, told GEN that he had been looking for next-generation therapeutic nanotechnology platforms as a venture capitalist for eight years prior to joining Bind. “We decided to invest in the Bind technology because it had the properties that could improve drugs, reduce toxicity, increase efficacy, and could work for a wide range of different drugs including small molecules, peptides, proteins, and siRNA.
“Additionally, it was technology that could be manufactured; nanoparticle technology is challenging to scale. Translating manufacturing from the bench to kilograms has been difficult to impossible for a lot of these technologies, but Bind has already addressed it effectively.”
Minick differentiated Bind’s approach from those of first-generation liposome-based nanoparticles explaining that the company’s “medicinal nanoengineering allows it to optimize properties in defined ways to achieve the biological result we want. We target through two different mechanisms: Biophysical properties of the nanoparticles are engineered to fit through gaps in blood vessels surrounding tumors and other disease sites. We also put a targeting ligand on the surface of the nanoparticle to bind to specific cell surface markers.” And a therapeutic payload is incorporated into the targeted nanoparticle.
The biocompatible and biodegradable polymer matrix for drug encapsulation used by Bind has been used in humans many times, according to Minick. “The PEG coating is the same PEG coating used in stealth liposomes, and it forms a hydration shell. The nanoparticles are the same size as a virus, but look like water droplets to the immune system, and the immune system ignores them. The breakdown products of PLA and PLGA are benign compounds: lactic acid and glycolic acid.
“In the case of our first drug our ligand binds to PMSA, a protein that is expressed on certain tumor cells such as prostate cancer cells as well as tumor neovasculature. The key differentiating property is that we can improve the underlying drug—docetaxel in the case of Bind-014. We have seen in animal models that we get up to a 20-fold increase in drug concentration in the tumor compared to administering the free drug.”
Minick also said that first-generation liposome-based nanotechnologies allowed “far fewer degrees of freedom and far fewer drugs relative to ours. It’s quite easy for us to change size, charge, etc.”
New ideas about how to optimize nanoparticles for drug delivery continue to emerge. One of the latest approaches involves nanoscale assemblies that can be activated and controlled through external stimuli, which its developers say may represent the next stage in multifunctional therapeutics.
For example, University of Rhode Island scientists reported the development of nanoparticle liposomes with embedded superparamagentic iron oxide nanoparticles. The particles cause drug release by making the liposomal shell leaky when heat-activated in an alternating current electromagnetic field operating at radio frequencies.
Meanwhile, as researchers continue to fine-tune multifunctional and multiplex nanoparticles, now on the horizon as the next-generation of cancer therapeutics, these technologies will no doubt continue to broaden therapeutic options for cancer patients.
Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].