Nanotechnology: A lifeline for drying pharma pipelines?

What has been nanotechnology's greatest contribution to the healthcare sector in the last 5 years?

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Oliver: Nanoparticle medicine has experienced substantial growth in the last half decade. Advances include new material chemistry for robust constructs, enhanced ligand co-targeting, formulation of true nanoparticles of ca. < 100 nm and a preliminary understanding of factors influencing systemic distribution. The recent introduction of nanoparticle formulations for intravenous administration has expanded their role as targeted drug carriers. In addition, nanoparticle enhancement of target organ specificity and linear release of payload exceeds that of traditional PEGylated or liposomal formulations.

Professor Jamie C. Oliver

Nanoparticles as small as ca. 35 nm have entered clinic testing, demonstrating minimised non-target extraction by the kidney and liver/spleen, which translates to an enhanced therapeutic window with low variations in systemic peak. These intentional changes in the pharmacokinetics/pharmacodynamics of the active drug may alter the pharmacology. For instance, a Phase I oncology study of a cyclodextrin-camptothecin nanoparticle (ca. 38 nm) developed at the California Institute of Technology (USA) demonstrated long-term stabilisation of tumours with repeated low doses, but was unable to generate partial responses at the maximum tolerated dose.¹ Therefore, the ability to modify the pharmacology or tolerability of specific drug classes could be a great benefit.

Vela: Although still far from a cure, the area of healthcare where nanotechnology has made its greatest contributions is cancer.

Adriana Vela

Nanotechnology is enabling new applications in the areas of molecular imaging and early detection, in vivo imaging, reporters of efficacy, multifunctional therapeutics and research tools. Significant advances have been made in all of these areas thanks to the funding awarded in 2004 by the US National Cancer Institute's (NCI) Alliance for Nanotechnology, which funded eight Centers of Cancer Nanotechnology Excellence and 12 Cancer Nanotechnology Platform Partnerships.

From a research perspective, the programme has already yielded more than 1000 peer-reviewed journal publications. From a clinical translation perspective, 50 diagnostics and therapeutic companies have collaborated with this programme and 34 new companies have been formed in the last 4 years — 10 of these new companies were formed just last year. Combined, they have a strong intellectual property portfolio of more than 200 disclosures and patents filed. Additionally, 8–10 clinical trials are associated with this programme and several companies are in pre-IND discussions with the FDA.

Drug delivery is another hot area where nanotechnology has made significant contributions. Today's drugs have issues such as systemic and non-specific delivery, side effects and the need for organic solvents. With nanotechnology, however, advances have been made towards improved localised delivery of drugs to tumour sites, improved efficacy and reduced side effects. Several nanotech-enabled drugs can now be found on the market such as Abraxane (Abraxis BioSciences), an albumin-bound paclitaxel for metastatic breast cancer; liposomal therapies Doxil, DaunoXome and Myocetp; and polymeric therapies, which include Genexol-PM and Oncaspar.

Outside of the NCI Alliance programme, nanotechnology has played a part in addressing an estimated 40%+ of compounds that have poor solubility, which results in reduced efficacy and also makes them difficult to develop. Elan has led the way with its acquisition of NanoCrystal Technology; the key benefits of the technology include, among others, improved biocompatibility, increased absorption rate, dose reduction, faster formulation of compounds, increased performance through variable administration routes (excluding injectable and inhalant delivery methods). Elan had its fifth product approved in late 2009 and has also licensed this technology to J&J, AstraZeneca, Roche and Bristol-Myers Squibb, to name a few.

Elsewhere, significant advances have also been made in diagnostics, through the identification of specific disease biomarkers and non-invasive imaging.

Liversidge: The launch of several commercially viable nanotechnology-based products must be, without question, the greatest achievement made during the past 5–10 years in the field of nanotechnology. For Elan Drug Technologies, we saw five licensed products launched using our NanoCrystal technology and achieved for our licensees who market these products annual in-market sales of more than $1.8 billion. These and other nanotechnology-based products have moved the technology from the academic curiosity that it was in the 1980s to one that can potentially deliver real solutions for the many compounds that are poorly water-soluble. In our own pipeline at least, we have many projects at various stages of development and during the coming years we expect they will make their way through development and approval.

Dr Gary Liversidge

Eaton: This is of course a regulated sector and whilst "nano" has been present for many years, the full impact is still years away. The biggest contribution of the technology to date has probably been in diagnostics, with the miniaturisation of devices along with developments in analytical instrumentation.

Professor Mike Eaton

The current impact for the pharma industry has been modest; probably more than $2 billion annually in sales. It is unrealistic to expect much more in the short term, given the corresponding slow introduction of biologicals onto the market from the lab. This subject is addressed further by the European Technology Platform in their roadmap.²

What challenges does nanotechnology pose to the pharma industry?

Oliver: The majority of the challenges facing the wide-scale development of nanotechnology relate to their unique distribution characteristics, physical chemistry, manufacturing processes and drug product characterisation. The slightest changes in particle size can substantially alter the biodistribution, renal excretion and pharmacodynamics of the active drug. Bridging nonclinical to clinical product development of nanoparticles may be especially difficult using current ADME models. To ensure consistent ADME, factors such as particle size, surface charge and surface chemistry will require robust characterisation with overlapping assays. Thus, it may be necessary to characterise "limits" to assure biologic activity as well as traditional qualitative "specifications" for the manufacturing of drug product.

Vela: The notion that companies must innovate to survive has become more commonplace as competitive pressures and economic volatility define the business landscape. For challenges affecting the nanotechnology industry, three general categories come to mind; intellectual property issues, regulatory issues and pharmacovigilance. Combined, these have the potential to create a perfect storm for the industry if not properly addressed.

Intellectual property assets are the lifeblood of companies in all industries. By 2011, the pharma industry faces the potential loss of approximately $70–$80 billion of drug revenues as various blockbuster drugs go off-patent. Critics argue that Big Pharma either fell asleep at the wheel by not building nanotech capabilities early enough or that they were more focused on shareholder profits than on innovative therapies. Add the current economic turmoil to this mix and we see pharma companies reducing headcounts to the tune of 69100 job cuts in 2009, up 60% from 2008. As a result, some are even changing their business model to include outsourcing of various functions to stay competitive, but will it be too late for some?

This is where leading biopharma or specialty pharma companies may have a slight advantage. In particular, those focused on nanotech-enabled discovery, development or platform technologies that increase benefits while reducing costs are now in a position of strength for licensing, outsourcing or other collaborative opportunities with Big Pharma. The challenge for Big Pharma will be to swiftly adapt to a new business model that has the right balance of in-house and outsourced processes. They will also need to make efficient use of resources to identify and incorporate nanopharmaceuticals and processes into their pipeline. This will be virtually impossible for companies that have cut their tech-scouting staff and risked giving away cheap buying opportunities to competitors. The challenge for small/medium biopharma and specialty pharma will be to figure out the best way to get on Big Pharma's radar. If they are not properly prepared with ample data, no amount of promised benefits will help and their funding will run out, as venture capitalist funding is predicted to decrease or remain flat in the near term.

With regards to regulatory issues and pharmacovigilance, safety and toxicity concerns continue to mount. An estimated $147-billion worth of nano-enabled commercial and consumer products were sold in 2007 and this amount it predicted to top $3.1 trillion by 2015, according to market analyst firm Lux Research.³ Concerns over the potential human health and environmental effects, however, could trigger a backlash on further development and commercialisation of product if concerns are left unchecked. The challenge is further complicated by the market's perceived slow pace of regulatory agencies, such as the FDA. While various FDA approved nano drugs have proven benefits well beyond existing therapies, some groups are not convinced that enough is being done to address the potential risks inherent specifically with nanomaterials, even though many of these concerns are felt by industry to be unfounded or over-hyped. This equally inhibits companies' willingness to be more transparent regarding their use as it makes it more difficult to raise capital and find partners to bring new innovations to market. Further, the FDA has recognised knowledge gaps and the need to develop a rational regulatory system for approving nano-enabled products. Many approaches are being analysed by agencies and active collaborations are in place to address these gaps and achieve progress.

The bottom line is nanopharmaceutical companies will need to work collaboratively with regulatory agencies at a very early stage of development to ensure a successful regulatory path and approval process. Once the product has hit the market, pharmacovigilance may kick into high gear in response to increased market pressure correlated with growth trends. As such, companies will need to be comfortable with the notion of being transparent and open with their information and safety data to win over the toughest critics. This will be a paradigm shift for the industry as a whole.

Liversidge: We have already seen that nanotechnology is having a significant positive commercial impact on a dozen or so commercialised products. However, this is only a tiny — nano-sized if you like — fraction of the number of drugs this technology could potentially rescue from abandonment. It is well accepted that pharma companies have a dearth of pharmaceutical products coming through development and that some 40% of compounds in development are poorly water-soluble. I would ask pharma companies to look at their own war chest of pipeline products and see if there are any hidden gems that were discarded because of their inherent poor water solubility properties. We have worked with a client on a product that is now a blockbuster; selling in excess of $1.2 billion in annual sales in the US alone.

Another challenge in further expanding the potential for nanotechnology is the lack of availability of skilled workers in this emerging space.

Eaton: The pharma sector is adaptable and can accommodate incremental changes. However, nanotechnology could enable radical innovation and open up new modalities for patients and the sector. Progress on nucleic acid based therapeutics, for example, has been slow because of delivery problems. Similarly, biologicals cannot address intracellular targets; neither can they enter the CNS. Progress here would challenge current thinking.

Fortunately, changes will not come overnight and provided you welcome open innovation, companies have plenty of time to adapt.

Will pharmaceutical manufacturing processes need to be adapted in any way to work with nanomaterials?

Oliver: Small molecule drugs have well-defined manufacturing requirements. However, manufacturing expectations for nanomedicines have yet to be clearly defined by regulators. To produce nanoparticle formulations under cGMP, it is reasonable to focus on several specific areas:

• Use of multiple robust approaches to validate particle size and particle volume. Evidence from clinical studies with nanoparticles suggests that even small changes in particle size can dramatically alter the amount of active drug at the target organ and have real physiologic thresholds. Therefore, numerous cross-conformational methods to measure particle size/volume are needed.

• Use of particle size exclusion and reprocessing to obtain consistent particle size. Nanoparticle variability can be well in excess of the conventional +10% limits required for drug products. Production processes using size-exclusion may be required to demonstrate comparability from lot to lot.

• Use of consistent potency terminology based on active drug substance. The manufacturing requirements for an approved product will need to control the concentration of active component and the total amount of nanoparticle in the final formulation.

• Surface charge (zeta potential) defines the electrical potential at the particle surface solution interface. High zeta potential generates stable suspensions, but may interfere with cell penetration or uptake. The ability to finely adjust zeta potential during formulation development will be necessary to ensure the nanoparticle passes a physiologic barrier (e.g., cancer cell) and remains in solution.

While additional factors must be addressed in cGMP, the characterisation of particle size and volume, exacting measurement of size, determination of surface charge and consistent drug loading will be challenges for manufacturing nanoparticle medicinal products.

Vela: Downstream manufacturing processes focused on scale up, packaging, marketing and such are likely to remain unchanged for companies incorporating nanomaterials into their products. Changes in upstream processes will be required to build up enough expertise to manage the tools and approaches in the discovery process, and also know-how to evaluate and handle materials from a safety and application perspective. Companies that have decided to outsource these upstream processes will still need to understand what they are dealing with and incorporate the necessary processes and collaborative efforts with regulatory agencies to move the product along the development pathway.

Liversidge: A number of methods are available to produce drug nanoparticles, involving either top-down processes based upon attrition, or bottom-up processes based upon molecular deposition. Each method brings with it scale-up and manufacturing challenges. Those approaches that use as much conventional equipment processes as possible have been the most successful. To date, no FDA-approved products are manufactured using the bottom-up approaches. The alternate and more established path for generating drug nanoparticles uses top-down processes.

For the development of nanoparticle-based solid dosage forms, conventional equipment and approaches should ideally be utilised. We have been very successful in using conventional equipment as much as is possible and have seen multiple dosage forms manufactured to commercial scale — tablets, liquid suspensions and, most recently, injectables.

Eaton: To date, manufacturing has managed. Until the future is scoped, it is hard to be sure what the problems might be as it depends on the specifics. Some countries have invested in a plant for nanomedicine manufacture, but to my way of thinking this is premature and a waste of money. Very few of the current novel therapeutic modalities will be successful and we will have to watch them carefully to anticipate the winners.

How do you think nanomedicines will be regulated in the future?

Oliver: It is likely that nanomedicines will be regulated in a similar fashion to those currently used with other large particle drugs/devices. I would consider liposomes and PEGylated technology as a possible predicate example of regulatory review. Therapeutically-focused teams with specialised support in nanoparticle manufacturing, quality and validation will continue to be the probable approach for regulatory review.

Vela: The likelihood that current regulatory processes will implement radical changes in the way they evaluate nano-enabled therapeutics and devices in the future is rather low. This is because of the significant parallel efforts and progress involving industry, academia and agencies being made in the area of nanomaterial characterisation. Moving forward, regulatory agencies will benefit from the growing knowledge base and, therefore, be in a better position to evaluate products for safety and identify potential risks. Philosophically speaking, many believe that regulatory agencies should regulate product, not science.

Liversidge: Nanomedicines will be regulated in the same manner as they are today, which is no different from other pharmaceuticals in that they have to demonstrate safety and efficacy. While nanomaterials may enjoy more attention because of the concern associated with behaviour of materials at the nano-scale, the fact that regulatory agencies throughout the world have approved nanomedicines, despite the concerns raised by popular media, shows that these concerns have been unfounded. Nanoparticulate-based products have been approved and launched in more than 100 countries.

Eaton: Regulation is a big issue for regenerative medicine and increasingly for in vivo diagnostics. The drug delivery or nanopharmaceutical area has been working with, and importantly talking to, regulators for many years. I anticipate fewer problems here.

What future advances in nanotechnology do you think will have a significant impact on the pharma and biopharma industries?

Oliver: The future of nanomedicines is at a pivotal juncture. There is a clear need for more robust and sensitive characterisation tests for particle size, distribution and volume. Identification of a diverse range of self-assembling structural components could potentially improve biologic characteristics, such as enhancing target organ distribution and eliminating non-target cell uptake. If successful, these advancements will allow nanoparticle constructs formulated for precise drug delivery.

Vela: It is no coincidence that more than $18 billion was invested in nanotechnology R&D in 2008 by governments and corporations worldwide, with substantial portions in the areas of health and medicine. With an ageing population and rising costs of healthcare, the focus is shifting from managing health to preventative measures. As such, preventative technologies, such as better diagnostic nanodevices, will be in high demand.

Nanotechnology also has the ability to get us closer to personalised medicine. Targeted therapeutics with smart drug delivery devices and theranostics will drive this trend forward. On the surface, these two trends are not likely to have a favourable impact on pharma's current business model, but they could if pharma adapts its business model to align more closely with scientific and market trends. The market will demand these technologies based on benefits and costs as compared to today's alternatives. Areas of nanotechnology advances with a direct benefit to pharma and biopharma are those that will not only further improve efficacy and reduce side effects of existing drugs, but that will enable a faster discovery process to eliminate non-efficacious drugs much earlier and with less investment. Similarly, there are nanotechnologies that will shorten the drug development process and get more drugs to market quicker. Just what the doctor ordered for the pharma industry...

Liversidge: I believe the next phase is the further development of parenteral nano-based products. Parenteral nanotechnology products with high drug payloads have significant potential — a recent example is Janssen's 1-month intramuscular depot product, Invega Sustenna, indicated for schizophrenia.

Looking further into the future, one could envision combining the concept of nano-sizing with other new approaches, such as tissue targeting and permeation enhancement. In addition, the whole aspect of particle morphology and its impact on nanosized products has yet to be explored. It is also probable that compound screening strategies will change. By having better tools to deal with compound solubility issues, solubility will no longer be a reason for rejecting a promising lead candidate. Lead selection can then be based on efficacy and safety alone. The era of nanotechnology is alive and well in the pharmaceutical industry. It will be interesting to see how things progress.

Eaton: Nanotechnology will have an impact on healthcare, but predicting the future is a difficult science. I personally believe it will be a "black swan" rather than an incremental process. One has to look at the major barriers now and current markets. For me, improving the transport of therapeutic macromolecules would be an area I would watch; progress here would open up new markets and help treat patients in a new way. These are not easy challenges, but it is what I would hope academics would focus on rather than derivative science.

Professor Jamie C. Oliver President & CEO, Peptagen

Adriana Vela Founder and CEO, NanoTecNexus

Dr Gary Liversidge Chief Technology Officer, Elan Drug Technologies

Professor Mike Eaton Executive Board Member, European Technology Platform on Nanomedicines

References

1. J. C. Oliver, et al. A dose-finding pharmacokinetic study of IT-101, the first de novo designed nanoparticle therapeutic, in refractory solid tumors. Abstract presented at the American Society of Clinical Oncology annual meeting (30 May–3 June, 2008; Chicago, USA).

2. www.etp-nanomedicine.eu

3. Nanomaterials State of the Market Q3 2008: Stealth Success, Broad Impact, (Lux Research, New York, USA, July 2008).