By Louis Garguilo, Chief Editor, Outsourced Pharma
How big can a singular change in perspective be? As big as a Copernican Revolution, you might say. Or more precisely, perhaps, how small can it be? If it’s the fundamental change that creates a metatheory moving biology to physics, it can be as small as building particles — or deconstructing them — atom-by-atom to bring new drugs to mankind. This is the big and small of nanomedicine (nano).
With the arrival of nano, there are three pillars of medicine steadying the hopes of patients: bio, pharma, and now nano. But don’t make the same mistake many people in pharma made during the advent of bio; nanomedicine is no pie-in-the- sky concept — it has arrived. “We can count 40 nanomedicine products on the commercial market,” says Laurent Levy, CEO of the Paris-based, oncology-focused nanomedicine company, Nanobiotix. “At least some 200 more are in clinical development.”
While scientific revolutions move thought in different directions, rarely is that direction backwards. With nanotechnology applied to drug development, though, we might end up further away from the need for precision medicines and return to the promise of mass production of drugs, including oncologics.
Whichever the ultimate direction, no discussion within the realms of drug discovery, development, and manufacturing — not immunotherapy or ADCs (antibody drug conjugates) — holds more potential scientifically, and perhaps revenue-wise, than that of nanomedicine. Says Levy: “Nano is the story. Now is the time to make sure all people understand.”
UP TO HERE-AND-NOW IN NANOMEDICINE
The first FDA-approved nanodrug was Doxcil (Sequus Pharmaceuticals) in 1995. According to the Journal of Controlled Release, the drug is important for at least these two reasons: prolonged drug-circulation time due to the use of nanoliposomes and drug release at the tumor.
“That’s the first approach of nano: Make an existing drug work better utilizing a nano-sized delivery system. Nanomedicine started in formulation development,” says Levy. By encapsulating a drug in a nano-liposome — purposely designed and smaller than ever before — you can change the distribution of the product in the body, hide the molecule, reduce toxicity, and increase efficiency in targeting tumors. If this sounds a lot like the minirevolution of antibody drug conjugates, Levy says nano can help overcome current limitations of ADCs … and offer alternatives.
As exciting as these applications of nano are, Levy, in a soft, conspiratorial voice, says the focus has expanded dramatically. “There is a new game in nano. We don’t need the drug anymore. The nanoparticle is the active principle.”
Heady stuff; but before going there let’s stay focused a bit more on where we are currently. To help understand the status quo, Levy references an article in the publication Nanomedicine, “The big picture on nanomedicine: the state of investigational and approved nanomedicine products.”
As if channeling our needs, it begins: “Developments in nanomedicine are expected to provide solutions to many of modern medicine’s unsolved problems, so it is no surprise that the literature contains many articles discussing the subject. However, existing reviews tend to … take a very forward-looking stance and fail to provide a complete perspective on the current landscape.”
For many of us, nanomedicine surfaced in 2005 when Abraxis BioScience’s Abraxane became the first nanodrug for breast cancer sanctioned by the FDA for the treatment of metastatic disease. Celgene’s 2010 buyout of Abraxis put an emphasis on the nano industry. The clinical and financial opportunities for nano were amplified with the FDA’s subsequent approval of the drug for the treatment of nonsmall cell lung cancer and for patients with advanced pancreatic cancer — one of the most difficult treatment areas in all medicine.
Detlev Biniszkiewicz was an early adopter of nano when he was VP of Oncology-Strategy, External Science & Licensing at AstraZeneca. In late 2013 he said, “The deal I am really excited about is the one we did with CytImmune [a clinical-stage nanomedicine company focused on multifunctional, tumor-targeted therapies]. Here we really want to push the envelope by loading one nanoparticle on two different drugs that have been shown to have synergistic effects in a preclinical model.” He added, “We would have had to develop two different drugs, and after years and years, hope to combine them. Instead, we are looking for nanotechnology to develop a truly disruptive innovation.”
Interestingly, while this example pulls the future directly into the present, it also introduces an old challenge for pharma — the loss of talent to burgeoning industries such as bio, and now, nano. For example, in April Biniszkiewicz decided to take what he learned at AZ to Surface Oncology Inc., a company focusing on immunotherapies, where he is now president and CEO. Indeed, according to the latest numbers published by the European Technology Platform for Nanomedicine (ETPN), there are already 400 start-ups devoted directly to nano in Europe, and as many as 200 in the U.S. Competition for nano-talent can only continue to increase.
"It is not about personalized medicine anymore, but mass medicine."
Back to the Nanomedicine report, it goes on to list hundreds of nano-related products commercialized or in the clinic. It also points out the difficulty in locating information on nanomedicine products. This has been partly due to the lack of a clear definition and categorization of nanomedicine as a unique product class. To solve this, the National Cancer Institute (NCI) and FDA have led efforts to standardize characterization of nanomaterials and the collection of information on nanomedicine products. NCI established the Nanotechnology Characterization Lab (NCL), which developed a “standardized analytical cascade that tests the preclinical toxicology, pharmacology, and efficacy of nanoparticles and devices.” Already,NCL has characterized over 200 nanomaterials from academia, government, and industry. And it now has a complement: The European Nanomedicine Characterization Laboratory (EU-NCL) was established in June, as a partnership of analytical facilities in France, Italy, Germany, Ireland, the U.K., Switzerland, and Norway.
Much earlier, the FDA Office of Pharmaceuticals Science (OPS) released a Manual of Policies and Procedures (MAPP 5015.9) instructing reviewers on gathering information on nanomaterial size, functionality, and other characteristics for use in a database. This manual provides a more inclusive definition of “nanoscale” and “nanomedicine” that encompasses any material with at least one dimension smaller than 1,000 nm. Why does size matter here? Most importantly because an object this small is uniquely capable of achieving properties and cellular effects not achievable without this nanoscale.
Marketwise, estimates vary because of this difficulty in categorization, but according to one analysis (BCC Research, “Nanotechnology in Medical Applications: The Global Market), the global nanomedicine sector was worth $53 billion in 2009, and it was projected to surpass $100 billion in 2014.
Levy himself seems involved in all parts of the discussion above. Nanobiotix’s first product — NBTXR3 — is nanoparticles designed for direct injection into a cancer tumor to direct and amplify the effects of radiation in the tumor and direct radiation away from surrounding tissue. NBTXR3 is currently in Phase 3 (scheduled to conclude in 2016) for patients with soft tissue sarcoma. Directly behind that indication are trials for liver and head-and-neck, rectum, and prostate cancers. A study commissioned by Nanobiotix estimates the market for this nanoparticle technology (NBTRX) at $5 billion to $6 billion annually.
Levy also plays a major role in the ETPN, acting as its vice-chairman. The ETPN is taking a step further than the NCLs by forming a Translational Advisory Board (TAB) of experienced nanomedicine professionals for companies to learn from and by establishing nanomanufacturing pilot lines. Finally, as we’ve seen above, Levy is also willing and able to explain where we are with what is to come. He does that, interestingly enough, with a reference to the advent of automobiles.
BACK TO THE FUTURE OF MASS MEDICINE
Levy shows me a slide of Henry Ford sitting in a prototype automobile at the turn of the 20th century. The text says, “If I had asked people what they wanted, they would have said faster horses.”
Levy explains that, although continuing and welcome, it’s not more improvements in biology (or chemistry) alone that will change the drug landscape. “Medicinal chemistry is the art of compromise,” he says quickly. “The same molecule has to be delivered and play a role in toxicity and efficacy, so you settle for the less-worse solution. However, if you have a drug like Doxorubicine and put it into a nano-liposome, you reduce the need for compromise on the molecule because the distribution and the toxicity are taken care of by the nanoparticle.”
Levy notes the current (biological) view of a cancer cell with a myriad of and complicated pathways. To produce an effect in the cell, you have to make manipulations on your molecule, but the complexity is limiting in terms of time, money, efficacy, and indeed scientific possibilities. “Biology is looking for an interaction with one molecule [the target] within a cancer cell in a body of billions of cells; you never know the complexity of interactions between your drug and multiple molecules within this body,” says Levy. “But look at the cell from a purely physical perspective; now you see identifiable objects, floating and moving in the cell as well as pillars and structures with physical behaviors. You can define physical constancy, like PH and physical mobility, temperature, pressure. You are redefining yourself and the concept of the target itself.”
The implications for cancers particularly, where there may be thousands of different cells to target, are clear. Today, drugs seem to have an effect on some of those cells, but not on others; some are “killed,” but others survive … and become resistant. According to Levy, this is an issue of conceptualizing within the highly variable world of biology, where every patient, even each cell, is different. “Now consider those same thousands of target cells receiving a nanoparticle providing a physical effect. That same particle will kill all the cells, with no exceptions." He adds, “It is not about personalized medicine anymore, but mass medicine.”
As perhaps the pièce de résistance, Levy adds the dimension of version upgrades. “You may start with a nanoparticle you want to heat to 50 degrees, but soon you can improve this function to 80 degrees. Nano allows for generation after generation of product. You can then combine functionality, just like an iPhone. We can add MRI visualization to the same particle that will heat, for example. You don’t do drug discovery; you plan innovation with product design. It is a completely different way to fight disease.”
THE BUSINESS FROM HERE TO THERE
The chief business officer at nanotherapeutic developer Cerulean Pharma, Christopher Guiffre, believes the drug industry will be greatly disrupted by this next generation of nanomedicine. “Five years from now I predict every Big Pharma will have nano programs,” he says. Indeed, a quick Internet search associates many pharma with the word nano. Merck is one of the biggest utilizers of nanoproducts to date, and last year Pfizer signed a deal with BIND Therapeutics Inc. (BIND) to collaborate on the development of nanoparticles, called Accurins.
"Medicinal chemistry is the art of compromise. The same molecule has to be delivered and play a role in toxicity and efficacy, so you settle for the less-worse solution."
So, at the same time that much of the healthcare industry seems focused on personalized medicine, nanomedicine may bring us back to the possibilities of a simpler, mass-medicine approach.
The fields of genetics, epigenetics, proteomics, and biomarkers have given us promising tools to work out our differences as biological entities and the differences in the biology of our diseases. (These tools, to a large extent, became the biotechnology industry.) A major reason for going in the direction of precision medicine (already evolved from personalized medicine, at least in nomenclature) was precisely because we couldn’t get mass medicine to work better. But precision medicine is complicated, time-consuming, can be invasive, and extremely expensive. What if nanomedicine re-permits the treating of disease with mass-produced, singular (nano) drug products? Besides the obvious benefits to patients, profitability could skyrocket for drugmakers, and healthcare costs could be drastically reduced across the board. Just to name one area of direct cost savings, compare the size of an API manufacturing facility to a nano-manufacturing facility. (Hint: It’s like comparing a huge factory to a large room, with less and less-expensive equipment.)
So all these (little) thoughts on nano surely add up to major contemplations on the future of medicine. Expect more editorial on this topic in future issues of Life Science Leader.