By Brian Orelli
Monday, July 30, 2018 | BioWorld | Actionable Intelligence, Incisive Analysis
It's been more than two decades since Doxil (doxorubicin, Johnson & Johnson), a liposome-based chemotherapy, was approved by the FDA. During that time, the field has evolved from simply protecting other tissue from highly potent drugs until they get to the site of the disease to increasing targeting and bioavailability.
"The field of nanomedicine has really had a resonance over the last five to 10 years," James Taylor, CEO and co-founder of Precision Nanosystems Inc., told BioWorld Insight.
Last year, Dublin-based Jazz Pharmaceuticals plc gained FDA approval for its bilamellar liposome, Vyxeos (daunorubicin and cytarabine), to treat adults with two types of high-risk acute myeloid leukemia, having gained access to the drug through its acquisition of Celator Pharmaceuticals Inc. a year earlier. (See BioWorld Today, June 1, 2016, and Aug. 4, 2017.)
Celator realized that a 5-to-1 molar ratio of cytarabine:daunorubicin maximizes synergy and minimizes antagonism. Unfortunately, cytarabine is rapidly cleared from the body while daunorubicin sticks around, so the solution isn't as simple as dosing five times as much cytarabine. Instead, Celator combined the two chemotherapies into a single nanoparticle to keep the optimal ratio while also increasing delivery to the bone marrow where leukemia cells grow. Fortuitously, the liposomes were even preferentially taken up by leukemia blasts, depositing the chemotherapies exactly in the cells they're designed to kill.
The company figured out that it needed a low – but not zero – amount of cholesterol in the liposome to allow for release of the drugs together, which wasn't possible with conventional liposomes that have higher cholesterol levels where daunorubicin leaked out. It also added copper to the nanoparticles to help retain the daunorubicin since the two molecules are known to interact.
"We call this the goldilocks effect," Lawrence Mayer, co-founder of Celator Pharmaceutical, told the audience at the third annual Precision Nanosystems Nanomedicines Symposium: "Shaping the Future" in New York earlier this month.
Also at the symposium, Martin Maier, vice president of research at Alnylam Pharmaceuticals Inc., highlighted patisiran, its RNAi therapeutic to treat hereditary transthyretin-mediated amyloidosis (hATTR) that's under review by the FDA. (See BioWorld, Sept. 21, 2017.)
As a double-stranded nucleic acid, RNAi drugs aren't particularly stable in the body nor do they get targeted to liver where patisiran needs to go to knock down expression of transthyretin, the mutated aggregated protein responsible for the symptoms of hATTR. To overcome both those challenges, Alnylam developed lipid nanoparticles to surround patisiran, although most of its earlier-stage pipeline focuses on GalNAc-siRNA conjugates, which appear to have better delivery and stability compared to nanoparticles.
By playing with the aminolipids in the nanoparticle, Alnylam was able to improve the potency of its first generation ALN-TTR01, which generated initial proof-of-concept data but was quickly put aside as it became apparent that the second-generation liposomes in patisiran (ALN-TTR02) made it substantially more potent.
"The evolution of this delivery technology for RNAi therapeutic delivery has been mainly driven by the discovery of novel amino lipids – ionizable lipids – which have improved in vivo potencies [and] improved efficiency of actual functional delivery of siRNA," Maier said of the lipid nanoparticle technology.
Alnylam also added PEG-C14 as a steric shield to keep the nanoparticles from aggregating in the vial, but the C14 version comes off rapidly after injection into the bloodstream, allowing for the recruitment of ApoE that targets the liposomes to the hepatocytes via the LDL receptor.
The overall use of nanoparticles to improve delivery and bioavailability has been relatively slow due to the complex nature of developing individualized nanoparticles with different requirements depending on the active drug and the nature of the delivery. But now companies are capitalizing on that knowledge base, developing nanomedicine platforms that are flexible and allow for easier development and scaling of manufacturing.
"As we bite off different problems and succeed on those, we can leverage those technologies," Precision Nanosystems' Taylor explained, highlighting that the company has about 100 different protocols that its customers can use depending on their needs.
Precision Nanosystems' Nanoassemblr technology uses microfluid continuous flow to control variables in the assembly of the nanoparticles. The company has three machines available that can scale depending on which stage of discovery a compound is in. The Spark machine can formulate microliters of nanoparticles in just seconds, while the Benchtop machine can scale between 1 milliliter and 15 milliliters for rapid prototyping and the Blaze can create batches up to 1 liter, enough for animal studies.
"We like to think that we're democratizing and lowering the barrier for people to get into these important technologies," Taylor said.
Nanoassemblr technology is currently in 19 of the top 25 pharmaceutical companies, helping Vancouver, British Columbia-based Precision Nanosystems secure a $6 million series B investment from existing investors 5AM Ventures, Telegraph Hill Partners and Rising Tide Fund last month. The company plans to use the capital to help expand its offering of clinical manufacturing solutions as its customers make their way into the clinic.
Likewise Nanosphere Health Sciences Inc. has developed a sequential manufacturing protocol using phospholipids capable of creating nanoparticles that are made up of 20 percent to 25 percent active ingredient, compared to 3 percent to 5 percent for the typical nanoparticle.
"Our Nanosphere delivery system is able to incorporate a wide range of pharmaceuticals, nutraceuticals and cannabinoids," Richard Kaufman, chief science officer at Nanosphere, told BioWorld Insight.
In addition to working with partners, Nanosphere recently launched its transdermal product, Nanoserum, that delivers THC directly into the bloodstream. The company is also working on intranasal and intraoral applications of the technology, which Kaufman said highlights the stability of its nanoparticles and the flexibility in manufacturing based on the type of barrier the nanoparticle has to pass. Typical commercial liposomes "tend to leak and aren't stable across mucosal membranes," he noted.