Drug Delivery Report

By Kate Atherton
Publishing Editor, PharmaVentures Ltd, Magdalen Centre, Oxford Science  Park, Oxford OX4 4GA, UK

Introduction

During the last six months  (May to October  2006), a total of 107 deals related to drug delivery have been recorded  in PharmaDeals® Agreements. Although this figure is lower than  that  for the same period last year, when 144 transactions were recorded,  the types of deal that  have been made,  and the types of technologies
and platforms that  have been the subject of these  deals, indicate that  drug delivery companies  continue  to play a vital role in the development and production of novel and innovative products.  These products,  and their associated technologies, have the potential  to deliver both new and pre-existing drugs to far greater  sections of the population, for whom these  drugs may previously have been entirely unsuitable.
This article draws on deal information  contained within PharmaVentures'  PharmaDeals® Agreements management tool to reflect on six months  of drug delivery deal
making. The PDA number  refers to the deal number  in
PharmaDeals®  Agreements.

Deal Makers

A full 89%  (95 deals in total) of all drug delivery deals
from this six-month period featured start-up  and emerging companies  (Figure 1). Global companies,  by contrast, participated in only eight deals: Pfizer, GlaxoSmithKline (GSK), Novartis  (in two deals, one with fellow global Schering-Plough); F. Hoffman-La Roche, Abbott Laboratories, Takeda Pharmaceutical and Merck &Co.
Not surprisingly, five of these  deals featured a collaborative and co-development element  while licensing and technology  access agreements and a business acquisition comprised the remaining  three deals (see Key Global Deals below).
Academic institutions and government bodies participated in 22 drug delivery deals between May and October,  primarily in order to aid the research and
development of efficient and convenient  methods of drug delivery in order to combat  diseases and other medical threats  that  can affect large numbers  of the population.
Five drug delivery deals had a potential  financial value in excess of US$50 M: the most valuable of these  was between RVX Therapeutics and Medtronic (PDA no.
24807).  In a deal potentially worth US$291 M, RVX granted to Medtronics exclusive worldwide rights to develop and commercialise its ReVas™ technology  for the local non-systemic treatment of cardiovascular disease.

Key Global Deals

Pfizer's acquisition of UK-based PowderMed represented a change  in direction for Pfizer, giving it access to a promising technology  that  delivers DNA directly to the
cells of the body's immune system and has the potential  to lead to a range of new vaccines for influenza and chronic viral diseases (PDA no. 25502).  In a press release, Pfizer's chief executive officer, Jeffrey B Kindler, announced that: "This acquisition is a strategic opportunity to enter the vaccine market and is part of our focus on broadening healthcare solutions for patients." The significance of this acquisition to the future of Pfizer was also apparent in the accompanying  statement of the company's vice chairman, David Sedlarz: "This acquisition is an example of the fresh approach Pfizer is taking to business development... With PowderMed's novel DNA technology  and its portfolio
of early-stage vaccine candidates, we are adding high- potential,  externally sourced product  candidates and technologies to our research and development portfolio."
While this transaction may prove significant for Pfizer's future interests,  it also highlights a possible leap forward for needle-free delivery systems. PowderMed's vaccine development program  is based on its Particle Mediated Epidermal Delivery (PMED) technology,  a needle-free delivery system that  delivers DNA-coated microscopic gold particles into the skin using pressurized helium gas. The particles penetrate the epidermal layer of the skin activating cells that  in turn trigger an immune response. The vaccines, which have potential  advantages over egg- based vaccines, can also be stored at room temperature and the system is sufficiently user-friendly that  self- administration  may be possible.
Global companies  Schering-Plough and Novartis entered into an agreement on 14 August to combine two of
their products  to form a single inhalation device for the treatment of asthma  and chronic obstructive pulmonary disease (COPD) (PDA no. 25006).  The product  will combine Schering-Plough's once daily inhaled corticosteroid mometasone and Novartis' once daily beta2-agonist indaceterol,  potentially eradicating  the need for asthma
and COPD patients  to use more than  one treatment. The combination  of corticosteroids  and long-acting  beta2- agonists is, according to the associated  press release, 'the fastest-growing segment of the worldwide asthma  market' for this very reason.  It is hoped  that  the product  will be used with, amongst other inhalers, Schering-Plough's Twisthaler®  delivery device, which is an inhalation-driven device that  operates with a propellant,  removing the need for hand-breath coordination.

 Academic  Institutions

Academic institutions entered into 19 deals between May and October  2006,  indicating continued efforts to combat some of the globe's most prevalent and chronic conditions, including cancers, HIV, Parkinson's and Alzheimer's disease, stroke and multiple sclerosis and influenza. New, reliable methods of population  control and aids for ending nicotine dependency also featured. Bodies from the US National Institutes of Health (US NIH) were involved in five of
these  deals.
Notably, four transactions could have potential  benefits for sufferers of Parkinson's disease and other severe neurological diseases. Amongst these  was a licensing agreement made in August between NuPathe  and the University of Pennsylvania for the LAD™ long-acting delivery technology  (PDA no. 25046).  This technology comprises a small, biodegradable polymer matrix, no
larger than  a grain of rice, which is positioned  below the skin, from where it slowly releases its drug (over a 1-3 month  period) before itself degrading. The controlled and sustained  release would improve the efficacy of
the treatment of Parkinson's disease and schizophrenia and reduce the risk of relapse in patients. The Michael J. Fox Foundation for Parkinson's Research granted NeuroDerm a fund of US$0.49 M in May to support
clinical work to develop a new transdermal skin patch for continuous delivery of Levodopa, the natural precursor of dopamine, which is deficient in Parkinson's disease (PDA no. 24222).  It is hoped  that  the patch,  through continuous transdermal delivery, will overcome the short half-life of Levodopa and should be able to minimise, or even reverse,
dyskinesias and other disabling late motor complications associated  with long-term  oral levodopa administration  in advanced  Parkinson's disease.

The Bioterrorism  Threat

The threat  of bioterrorism,  against  civilian populations and armies in the field, has impacted  on the US Government's involvement in the pharmaceutical industry. During the
last six months,  the US Department of Defense has entered into two deals with the aim of combating this threat. In July, it awarded LigoCyte Pharmaceuticals a contract  worth US$2.3 M to continue  its validation of its third-generation mucosal anthrax vaccine (PDA no. 24682). LigoCyte's dual-antigen vaccine includes a protein antigen to protect  against  a toxin released from the bacteria,  and
a bacterial capsule antigen  to help the body fight the infection itself. This vaccine has a number  of advantages over other anthrax vaccines currently being evaluated
by the US government: the dry powder  formulations  are stable, easy to handle; it does not require cold storage
and so can be transported to remote  areas; the intranasal, needle-free delivery route  is less invasive and could be
self-administered;  only a single dose would be required, in contrast  to the six-dose regimen currently available. In October,  the US Department of Defense awarded Inovio Biomedical a grant of US$1.1 M to develop applications of its electroporation-based gene delivery technology  for vaccination against  infectious disease, including potential bioterrorism agents  (PDA no. 25586).

Nanotechnology

Nanotechnology continues  to account  for a significant number  of drug delivery deals; 9% of deals over this six- month  period focused upon products  which have, in some cases, been given a new lease of life due to the possibilities offered by delivery using nanotechnology. In particular, recent deals highlight the significance of nanotechnology's contribution  to producing  new formulations  that  enable
the delivery of drugs transdermally,  or the delivery of drugs that  would otherwise  be insoluble.
Global company Abbott Laboratories, in a partnership with AstraZeneca, was granted US rights in July to use Elan's proprietary NanoCrystal®   technology  (PDA no.
24681).  This robust drug optimisation  technology,  which enables solubility, can be incorporated into common dosage  forms, including tablets,  capsules and inhalation devices. This agreement would use Elan's NanoCrystal® technology  to develop and commercialise a single
fixed-dose combination  product  containing  the APIs
in Abbott's TriCor®  145 (fenfibrate) and AstraZeneca's Crestor®  (rosuvastatin calcium) products.  Nanoparticles can also be used in pulmonary drug delivery. In May, the Australian  Research Council awarded Singapore-based
NanoMaterials Technology (NMT) and the University of Sydney a grant worth US$333,000 to explore the market potential  of drug delivery by inhalation aerosols using nanoparticles (PDA no. 24173).
Bridgehead Holdings International acquired the Asian rights in May to two reformulated cancer therapeutics which significantly reduce the toxicity and side-effects associated  with the current versions of docetaxel and paclitaxel which use detergents to
breakdown their compounds (PDA no. 24113).  In addition to serious side-effects,  this bleach also requires the immune system to be suppressed for three days, posing serious
risks for cancer patients. The new formulation  effectively removes the toxicity while, at the same time, enabling significant dosage  increases.

Methods of Delivery

Methods  of delivery varied considerably and included patches,  sprays, inhalable products,  liquids, gels, tablets,  as well as more unusual technologies.
Five deals focused upon patches,  including the NeuroDerm patch for Parkinson's disease discussed above. These included a joint development agreement made
in May between Nitto Denko  and Eisai concerning  a transdermal adhesive preparation of Aricept®  (donepezil hydrochloride), a drug currently indicated for mild-to- moderate Alzheimer's disease in tablet form (PDA no.
24221).  This project aims to develop a transdermal patch formulation  using Nitto Denko's proprietary transdermal delivery technology.  The value of patches  for pain relief is shown by Lavipharm Laboratories' fentanyl transdermal system, which can manage moderate to severe pain.
In August, DAVA Pharmaceuticals agreed  to be the exclusive marketer  and distributor of the system in the US (PDA no. 25135).
Sprays, which deliver drugs safely and rapidly by
nose or by mouth,  have increasingly been developed  by companies  seeking user-friendly and effective alternatives to more invasive and unpleasant treatments. Five deals involved such sprays and all but one of these  sprays was developed  with the diabetes  patient  in mind. The potential improvement in the patient's quality of life is clear.
In August, ShinNippon Biomedical Laboratories' two subsidiaries, Translational Research and Bioactis, signed an agreement for the licensing and supplying
their patented nasal drug delivery technology  in the field of endocrinology  to Tokai Pharmaceuticals (PDA no.
24955).  This technology,  an injection delivered through the nasal membrane, could be used for insulin or morphine. Between June and October,  Cardinal Health participated in three deals involving sprays containing  insulin products. The first, in June, saw Cardinal Health agree to formulate and fill clinical trial batches  of Generex Biotechnology's Oral-lyn™, a proprietary oral insulin spray product  (PDA
no. 24594).  Furthermore,  in September, Cardinal Health agreed  to distribute  Generex Biotechnology's new Glucose RapidSpray™  product  in the US (PDA no. 25295).  This product  delivers a fat-free,  low-calorie glucose formulation directly into the mouth  where it is rapidly absorbed into the  gave Bentley Pharmaceuticals capacity at Cardinal Health's new North Ralegh facility, thereby enabling the scale-up and manufacture of clinical supplies of Bentley's intranasal product  candidate which delivers insulin directly and discreetly through nasal mucosa (PDA no. 25305).
Six deals focused on inhalable products.  These included MAP Pharmaceuticals' Tempo™  inhaler, a device which automatically adjusts to each patient's unique inspiration pattern, without  electronics, and is very easy to use.
In May, Xemplar Pharmaceuticals agreed  to serve as the exclusive manufacturer of Tempo™  inhaler products currently being developed  for the treatment of asthma  and chronic obstructive pulmonary disease (COPD) (PDA no.
24274).
In July, Antares  Pahram signed a co-development agreement with the Population Council to develop contraceptive formulation  products  containing  Nestorone® by using Antares' proprietary, advanced  transdermal (ATD™) gel platform (PDA no. 24814).  There are a number of advantages to this form of contraception: it is clear
and cosmetically acceptable; it is safer than  most oral contraceptives; it is convenient;  it is attractive  to women who have trouble taking oral contraceptives; it can be used when breastfeeding.
More unusual methods of drug delivery included the development of a chewing gum for the treatment of type
2 diabetes  mellitus and obesity. Generex Biotechnology's buccal drug delivery platform technologies will be combined  with Fertin Pharma's expertise in gum base formulations  to develop a chewing gum that  will deliver metformin  into the body via the inner lining of the mouth
(PDA no. 24396).  This would avoid many of the unpleasant side-effects associated  with taking this drug in tablet
form and will offer a far more attractive  option to young diabetics. Other products  include the BEMA™  disc, which delivers pain relief to cancer patients  directly through the inner cheek (BioDelivery Sciences International  acquired
all non-US rights to the product  from QLT USA in August) (PDA no. 24931),  and two toothpastes. PharmaSpritz Corporation and AZ Technologies will develop the F.A.S.T. toothpaste for weight loss and Pearly Dreams for sleep inducing (PDA no. 25121).

Conclusion

A broad range of delivery devices and technologies have formed the focus of drug delivery transactions during
the last six months,  ranging from inhalers and injectors, transdermal patches,  creams and gels to liquids and tablets, foam and film, chewing gum and toothpaste. While the aim remains of adapting old products  to new methods of delivery in order to expand their market life, it is also clear that  producing  a product  that  is easy to use, self-administering if possible, painless and convenient  is a significant factor.