When Celgene Corp. paid $2.9 billion plus potential milestones for Abraxis BioScience Inc. in 2010, by far the largest ever exit for a nanomedicine-focused biotech, numerous industry observers shared the concerns of Bernstein Research analyst Geoffrey Porges. “At first blush,” Porges wrote, “$3 billion-plus seems expensive for a business with essentially flat sales of around $360 million.”

Celgene did the deal primarily to acquire Abraxane, an albumin-bound nanoparticle version of the chemotherapeutic paclitaxel for the treatment of metastatic breast cancer after chemotherapy, widely regarded as the first and still only polymeric nanoparticle drug on the market [See Deal]. Celgene believed Abraxane could obtain approval in multiple solid-tumor indications, with blockbuster potential ([A#2010800131] and Also see "Celgene Flexes Its Muscles" - In Vivo, 1 March, 2011..

With each passing month, it seems, Celgene’s bet looks better and better. In October 2012, Abraxane was approved as a first-line treatment for non-small cell lung cancer (NSCLC). Soon to follow were positive results from a Phase III study in melanoma and then solid data from a Phase III study in pancreatic cancer.

These successes mark significant milestones in the passage of nanodrugs from experimental and academic programs to products. In theory, these medicines will deliver therapeutic payloads at infinitesimal scale – generally less than 100 nanometers – encased in lipid coats or conjugated with polymers.

Think Small

There’s no broad commercial proof yet, but advocates of the field say small might end up better than big when it comes to the size of therapeutic molecules. They say reducing an active agent and its formulating backbone to atomic scale can increase a drug’s solubility, improve bioavailability and enable transport across barriers to a target.

“This second generation of nanotechnology for targeting and delivery [of medicines] opens up a whole new frontier,” said Terry McGuire, founding partner at Polaris Venture Partners. Polaris is closely aligned with entrepreneurial Massachusetts Institute of Technology chemical engineer Robert Langer and his former students, who have been exploring the therapeutic permutations that polymeric nanoparticles enable. Polaris backs several prominent nanomedicine biotechs, some with ties to Langer and his affiliates. McGuire expects the field to overcome industry skepticism as nanotech generates later-stage assets over the next few years.

One of Polaris’ portfolio companies, Cerulean Pharma Inc., presented data in mid-March 2013 that could be a bellwether for next-generation developers. Its compound CRLX101, a polymeric nanoformulation of cytotoxic cancer drug camptothecin, is wrapping up a pivotal Phase II study as a monotherapy for advanced NSCLC following one or two prior regimens of therapy. Since camptothecin’s discovery in 1966, two analogues have been widely used as anticancer agents, but the more potent original drug proved difficult to solubilize, leading to dangerous buildup in healthy tissue.

Cerulean’s camptothecin nanoformulation, acquired in a 2009 deal with Arrowhead Pharmaceuticals Inc.’s Calando Pharmaceuticals Inc., appeared in a Phase I study to avoid the previous side effects, potentially leading to greater anti-tumoral potency. [See Deal]

A successful CRLX101 trial should embolden the pharmaceutical industry, which to date has otherwise been unwilling to forge development alliances with nano-focused biotechs. Four recently launched companies – Tarveda Therapeutics Inc., Kala Pharmaceuticals Inc., [Qualiber Inc.] and [Uroboros Technologies LLC] – are looking for positive industry signs as they push ahead into a new age of advanced nanomedicine.

The programmable characteristics of next-generation polymeric nanosystems now being studied aim to add enabling properties to therapeutics, from increased efficacy with lower toxicity for anticancer agents to a theranostic future in which circulating nanoparticles seek out and destroy disease cells through a combination of diagnostic surveillance and therapeutic payload in a single nanoparticle.

BCC Research LLC is bullish on the anticancer nanomedicine market, predicting growth from $5.5 billion in 2011 to $12.7 billion by 2016. That seems a bit optimistic, considering no global pharmaceutical company has yet entered into a development alliance with a nanotech biotech, and that Amgen Inc.’s tie-up this past January with polymeric nanoparticle drug developer Bind Biosciences Inc. to share development of a novel polymeric anticancer nanoagent was the first early-stage deal in the field [W#201320018]. (However, Bind followed up that deal with a second collaboration around its Accurins technology with Pfizer Inc. on April 3). ([A#14130402003])

Nano Grows Up

For some 40 years scientists have experimented with biocompatible nanomaterials to reformulate therapeutic agents and interface with disease sites in novel ways. Liposomal encapsulations were the first nanomedicines to become products, and they remain the most widely pursued. The lipid bilayers that form a liposome – basically a lipid sack around an inner core – can encapsulate soluble drugs or drug crystals, reducing their clearance from the body and boosting their ability to get through water-impervious membranes to reach disease-target cells.

Liposomal reformulations of existing agents not only improve their pharmacokinetics, but also create new chemical entities with corresponding extensions of product life. The first FDA approval for a nanomedicine came in 1995, when the agency green-lighted the liposome-encapsulated form of the chemotherapeutic Doxil (doxorubicin). About a dozen other liposome-encapsulated formulations of existing drugs have won approval since, as cancer therapeutics, anti-infectives and vaccines.

FDA has encouraged such development, especially in oncology, by fast-tracking clinical trials, but several studies have come up short. Most recently, in January 2013, Celsion Corp.’s Phase III liver cancer trial of ThermoDox, its liposomal formulation of doxorubicin in combination with heat-based treatments such as radiothermal ablation, failed to meet its endpoints. The company had theorized heat would open leaky tumor vasculature further – theorized to be the opening through which Doxil passes into tumors – and boost uptake and efficacy of its drug-containing liposomes. It did not seem to work.

Despite setbacks, several biotechs are pressing on. For instance, Qualiber is developing a proprietary liposomal nanopackage as a new form of the chemotherapeutic gemcitabine. The North Carolina biotech also is experimenting with liposomal coats to deliver oligonucleotide agents such as siRNA, which have not succeeded as drugs in their natural form to date.

Over the past decade, academic laboratories and companies like Abraxis have explored the use of nanopolymers to reformulate existing drugs and design new molecular entities. Bio-inert polymers, most often composed of low-molecular-weight polymers formed of polyethylene glycol (PEG), have numerous theoretical advantages over liposomes. They provide more control over scale-up and manufacturing – which has plagued Doxil – and more precision in particle size, shape and surface charge, lending them a wealth of combinatorial possibilities in therapeutics and other medical products.

Polymeric reformulation aims to usher drugs into presently undruggable sites. For example, Kala is targeting diseases of the eye and other organs where mucosal barriers block delivery of some drugs. Others look to improve accumulation of active agents at disease sites while avoiding healthy tissue – which is one of Blend’s goals with a portfolio of platinum anticancer drugs in polymer matrices. In theory, nanopolymers also could conjugate several agents in a single drug or enable controlled release of a drug in response to a patient’s pathophysiological changes.

Betting On Nano

“Nano” was something of a fad, particularly in materials science, earlier in the past decade. Technological promise and capital market interest in nanotech led Aymeric Sallin to launch NanoDimension, a Swiss venture capital firm that focuses solely on nanotechnology. Before the financial crisis, Sallin raised a small €45 million ($60 million) fund. It has invested in three nanomedicine start-ups, Blend, Bind and Selecta Biosciences Inc., along with four nanomaterials and nanoelectronics ventures. [See Deal][See Deal][See Deal][See Deal][See Deal][See Deal][See Deal]

Sallin lauds nanopolymeric formulation for the control it offers over particle size, composition, stability, surface charge and other parameters to engineer and optimize better drugs. “It’s like having a whole new set of dials on the radio as you work to fine-tune the signal,” he says.

Proof awaits that they can work as advertised. Omid Farokhzad, who trained in Langer’s lab and now is a professor at Brigham and Women’s Hospital and Harvard Medical School, co-founded Bind, Blend and Selecta with Langer and others. He thinks success for lead candidate BIND-014, a nanoparticle formulation of the chemotherapy docetaxel now in Phase I clinical testing in solid tumors, will prove a watershed event for the new field of targeted and controlled-release nanoparticle drugs. Bind’s nanopolymeric Accurins circulate, aggregate in tumor tissue targets, and release their cytotoxic payload over time.

“Unlike a lipid sack,” Farokhzad says, “a polymeric system can be targeted to hone to the disease site and give a tunable release,” by attaching a tumor-targeting ligand to the particle surface, shielding the surface to evade immune response, and engineering the polymeric matrix encapsulating the drug to break apart inside the cell at a controlled rate.

Nanopolymers might open medical doors that presently are locked. For instance, one of Kala’s programs aims to develop a topical nanoformulation that permeates and crosses the tear mucin into the eye and travels from there to treat retinal diseases such as age-related macular degeneration, currently treatable only via painful injections. Bind also owns rights to create oral versions of injectable nanoagents based on work from Farokhzad’s and Langer’s labs.

(This article was adapted from the original version appearing in the March issue of START-UP magazine. For information about START-UP, contact customer care at 800-332-2181.)

Celgene’s Bet On Abraxis Helps Spur Host Of Nanomedicine Start-Ups

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