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Nano-enabled drugs:once bitten, twice shy?

Jon Howells and Carys Lloyd
European Biopharmaceutical Review, page 60 - 62
December 2009

Nanotech-based reformulations of existing drugs have failed to inspire Big Pharma – but truly nano-enabled drugs offer real potential for innovation and companies ignore them at their peril.

Major pharmaceutical companies have launched a handful of drugs with nano-characteristics in recent years, but revenue has been slow to materialise. However, truly nano-enabled drugs – designed from first principles and structurally engineered to deliver particular drugs to targeted sites – promise revolutionary treatments and impressive profits. By assuming that  such designer drugs will fare no better than the first generation of drugs with nano-characteristics, Big Pharma may have taken its eye off the ball and is at risk of losing the race to develop the next generation of medicines. Pharmaceutical companies will need to transform their strategy, culture and skills if they are to ride on the success of nanotechnology and produce the blockbuster drugs of the future.

For the past few years, nano-enabled drugs have been hailed as the next major generation of new medicines to reach the market. Due to their small size, their behaviour is determined by their dimensions, not just their chemical properties; consequently, they have astounding properties unseen in any other type of material. They can be tailored to be absorbed into the body quickly, enter specific cells and release a payload of drugs in a controlled way. Such targeted drug delivery offers new hope to, for example, cancer, AIDS and hepatitis patients who – when undergoing traditional treatment – have to endure distressing side-effects due to the inefficient cell targeting of their potentially toxic drugs.

Seven years after the US National Institutes of Health (NIH) allocated around $45 million for medical nanotechnology research (1), and six years after George W. Bush allocated $3.7 billion to the research and development of nanotechnology (2), it is sobering to learn that major pharmaceutical companies have not shared the appetite of Western Governments for nanotechnology research and development. Recent studies have found that Big Pharma is committing only token amounts to nanotechnology research (3). Consequently, the small number of nano-characteristic drugs developed by Big Pharma is merely incremental in nature, being liposomal or nanocrystalline reformulations of existing generic drugs (4). Using milling, high-pressure homogenisation and controlled precipitation techniques to create nanoscale particles of drugs has produced medicines with only modestly improved absorption and reduced toxicity characteristics. Such reformulations have not led to significant returns on investment, as approval bodies such as the UK’s National Institute for Health and Clinical Excellence (NICE) often recommend nanocrystalline and liposomal drugs to be substituted by cheaper generic comparator drugs (4).

Major pharmaceutical companies seem to be on the verge of losing interest in nano-enabled drugs; unimpressed with the profit margins of incremental drugs with nanocharacteristics,they have not seen a need to modify their strategies to find the next big blockbuster. They have therefore been content to sit back and let other companies take the lead in nanotechnology research and development. By letting nano-enabled drugs slip off its radar, Big Pharma might have failed to recognise the step-change and improved performance and profitability that such drugs could potentially offer. Few companies have launched trulynano-enabled drugs yet (5,6), but it is anticipated that several products will be launched on the market in the near future (7,8). The market for these drugs – designed from first principles and structurally engineered to deliver particular drugs to targeted sites – is predicted to rise steeply after 2012, reaching potentially $220 billion by 2015 (9).

Big Pharma has been facing diminishing returns on its research and development investment for several years (10,11), and is anticipating even more substantial drops in revenue in the years to come when the patents on its blockbuster drugs expire. It clearly needs a drastic change in its approach if it is to revitalise its product pipelines. Nano-enabled drugs could inject new life into the portfolios of pharmaceutical companies, and revitalise their pipelines. However, large strategic and technological hurdles will need to be overcome if they are to  share in the growth and profits promised by such drugs.

Major Pharmaceutical companies need to incorporate targeted drug delivery into their vision
The research and development activities of Big Pharma are almost entirely focused on developing new chemical formulations with therapeutic value. Research activities to improve the delivery of these formulations to their target cells are either given a lower priority or neglected completely (3). Seeing that one of the main near-term impacts of nanotechnology will be on drug delivery – rather than drug discovery – it is not surprising that major pharmaceutical companies have struggled to fully grasp the value of nanotechnology. Only one sixth of Big Pharma companies have explicit strategies for nano-enabled drugs (3), and most view structurally-engineered nanotech drugs as something that might only become important to pharmaceutical companies within a decade or so (12,13).

One opportunity for pharmaceutical companies is to assign a higher priority to targeted drug delivery if it is to develop nano-enabled drugs. Drug delivery leaders need organisational support, resources and a clear mandate to perform exploratory research into nanotech-based drug delivery mechanisms. With the correct objectives and resources, there is the opportunity to generate a sustainable nano-enabled drug product line.

Develop synergistic collaborations with nanotechnology companies
A plethora of nanotechnology companies are active in developing novel nano-engineered structures that could be used for targeted drug delivery. Dendrimers, carbon nanotubes and nanopolymers are all structures that have been identified as scaffolds that could traverse targeted cell walls. However, the therapeutic value of such structures relies on incorporating traditional drugs within them. For instance, the world’s first polymeric nanopharmaceutical, Abraxane, is an amalgamation of a drug discovered in 1967, grafted onto a nano-engineered polymer.

Big Pharma is sitting on hundreds of patents that might benefit from the incorporation of nanoparticles. In order to match up suitable nanostructures to particular drugs, Big Pharma must collaborate with nanotechnology companies. Although some collaborations exist already between the two industries (14,15), many more partnerships will be necessary in order to accelerate the development of nanoenabled drugs and launch them on the market. Just as Big Pharma invested in mega-mergers and acquisitions of biotech companies when the value of biopharma was realised at the beginning of the 1990s, it will need to embark on new investment and collaboration programmes with nanotechnology companies. If the market follows previous trends seen when a new technology is introduced – such as biopharma – the successful early adopters will reap the rewards.

Invest in metrology
The research and development activities of Big Pharma are almost entirely focused around high-throughput screening and combinatorial chemistry methods to identify and synthesise new chemical formulations with therapeutic value. However, the research tools and techniques used to nano-engineer drugs are more closely allied with the semiconductor industry, where chemical vapour deposition, plasma arc discharge and laser irradiation are routinely used to produce nanostructures. Sophisticated inspection tools such as tunnelling electron microscopy and ellipsometry are also required to validate how nanostructures interact with biological samples. Few Big Pharma companies can currently claim to have the materials science expertise that truly novel nanotech-based drug development requires.

The pharmaceutical industry must be prepared to invest in recruiting skilled metrologists and specialised metrology equipment in order to develop, manufacture and inspect nanostructures such as nanotubes and buckminsterfullerenes. Even if they choose to develop nano-enabled drugs with an external nanotechnology partner, it is still important that Big Pharma has its own in-house metrology experts and inspection systems in order to monitor the quality and safety of any codeveloped nanostructures.

Nano-enabled drugs have much to offer the pharmaceutical industry, but Big Pharma will need to embrace new strategies, cultures and skills if it is to keep abreast of the new technology. Industry and governments are working hard to help nanotechnology jump the ‘technology adoption gap’, and when successful, the next generation of medicines will provide enhanced efficacy. Profitable opportunities exist for forward-thinking pharmaceutical companies willing to implement nanotechnology-centred product development strategies.

Nanotechnology companies are already leading the way in bringing these next-generation medicines to the market. How much longer can Big Pharma afford to stand on the sidelines?

A recent nano success story
AlphaRx, Inc presented positive preclinical data on ZysolinTM Inhalable polymeric Nanoparticles at the Controlled Release Society Annual Meeting in July 2009. ZysolinTM is a tobramycin compound encapsulated in AlphaRx’s nano drug delivery platform, and is hoped will be an effective treatment against Gram-negative pneumonia. Tobramycin has a long-standing and proven clinical record, but as an injectable drug, is not highly absorbable. ZysolinTM increases the drug concentration of Tobramycin inside human macrophages, thus improving its antibacterial activity against intracellular Klebsiella, Pseudomonas aeruginosa and Staphylococcus bacterial strains in pneumonia patients.

 

Jon Howells is a pharmaceutical technology consultant helping clients realise value through development of novel delivery devices for pharmaceutical products, guiding them through from feasibility to market launch. Jon has 25 years experience working in the industry, mostly while at GlaxoSmithKline R&D and manufacturing. His areas of expertise include development of drug device combination products and analytical testing.

To email Jon Howells, click here.   

Carys Lloyd is a Technology and Innovation consultant at PA Consulting Group. She helps clients implement new technologies, which lead to improved products and processes, and works with clients active in a range of sectors, from Healthcare through to Consumer Products. One of her areas of expertise is developing metrology tools that can be used to inspect surface features and measure the collective properties of fast-moving particulates. Prior to joining PA, she completed a PhD in the Shock Compression of Condensed Matter at the University of Cambridge (UK).

To email Carys Lloyd, click here.

To email the Healthcare Team, please click here.


To visit our Technology and Innovation pages, please click here.


References and Notes

1. AAAS Report XXVI: Research & Development, 2002, http://www.aaas.org/spp/rd/xxvi/chap23.htm

2. National Nanotechnology Initiative News announcement, 2003,

http://www.nano.gov/html/news/releases/PresSignsNanoBill.htm

3. Why Big Pharma Is Missing the Nanotech Opportunity, Lux Research, 2005,

http://www.luxresearchinc.com/

4. Fisher M, Nanotechnology: the next silver bullet? Pharmaceutical Technology Europe, 2009

http://www.ptemag.com/pharmtecheurope/Manufacturing%20&%20Processing/Nanotechnology-the-next-silverbullet/ArticleStandard/Article/detail/605695

5. Launched micelle drugs include Genexol by Samyang (2008, Korea only) and Estrasorb by Novavax (2003).

6. Launched polymeric nanoparticles include Abraxane by Abraxis (2005), Neulasta by Amgen (2002), and Renagel by Genzyme (2005)

7. Vivagel, a dendrimer drug manufactured by Starpharma, is currently undergoing human trials and is hoped to be launched in 2010. Avidimer Therapeutics aims to commercialise its first dendrimer product in 2014-15

8. Medicelle by NanoCarrier, Flucide by NanoViricides, Basulin by Flamel Technologies/Bristol Myers Squibb, DO/NDR/02 by Dabur Research Foundation and DDS-2001 by LaboPharm are all Micelle products currently undergoing development

9. The Nanoparticle Drug Delivery Market, Cientifica, 2007

10. Outlook 2008, Tufts Centre for Drug Discovery, 2008, http://csdd.tufts.edu/InfoServices/OutlookReports.asp

11. Outlook 2000, Tufts Centre for Drug Discovery, 2000,http://csdd.tufts.edu/InfoServices/OutlookReports.asp

12. McCarthy V, Pharma Explores Business Opportunities for Nanotech, Nano World News, 2006,http://www.nsti.org/news/item.html?id=43

13. Choi CQ, Big pharma neglecting nanotech, NanoWorld, 2005 http://www.aegis.com/news/upi/2005/UP050206.html

14. Elan Corporation have licensed their nanoparticulate technology to major pharmaceutical companies including AHP, Merck, Johnson & Johnson, Astra, BMS, Abbott and Roche,http://newsroom.elan.com/phoenix.zhtml?c=88326&p=irol-pressroom

15. Flamel Technologies have licensed their Medusa platform, a self-assembled poly-aminoacid nanoparticles system, to major pharmaceutical companies including Merck Serono and Bristol-Myers Squibb http://www.flamel.com/techAndProd/medusa.shtml 

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