A synthetic vaccine form of Ab42, AN-179, was

prepared and PDAPP mice (an animal model gen-

etically engineered to develop AD-like pathol-

ogy) were immunized through intramuscular

vaccination.

Animal studies demonstrate successTwo sets of experiments were performed to test

the relative merits of this approach.

• Young (six weeks: when the mice are too

young to develop amyloid deposition and

associated brain damage) PDAPP mice were

used to test the vaccine in preventing the

development of Alzheimer-like pathology

• Older mice (11 months: when amyloid depo-

sition and associated damage is already well

established) were used to test the ability of

the vaccine to treat existing pathology

Quantitative immunohistochemistry demon-

strated that AN-1792 immunization of the young

mice essentially prevented the development of

amyloid plaque deposition and surrounding

neuropathology. At 13 months, the group treated

with AN-1792 had statistically significantly less

amyloid plaque than the control groups. In fact,

virtually all of the mice immunized with AN-1792

had no detectable amyloid deposits in their

brains, in marked contrast to the control groups.

The study in older mice showed that the vac-

cine could also significantly reduce the extent and

progression of Alzheimer-like pathology. The amy-

loid load in brain tissue at 15 and 18 months, as

shown by quantitative imaging, was significantly

lower in AN-1792 vaccinated mice than in control

mice. Furthermore, 18-month old vaccinated mice

had fewer plaques than 12-month old untreated

mice, suggesting that the vaccine facilitates the

removal of preformed plaques. Beta-amyloid

ELISA analysis of the older mice was consistent

with the immunohistochemical observations.

Exciting prospectsThese results show that immunization with AN-

1792 can both prevent the deposition of amyloid

plaque and enhance the clearance of pre-formed

plaque, at least in genetically engineered PDAPP

mice. According to Dale Schenk, vice-president of

neurobiology at Elan, ‘although our precise under-

standing of the immune response here is unclear,

we believe that antibodies raised by AN-1792 can

cross the blood–brain barrier in sufficient amounts

to trigger an immune response against the amy-

loid plaques, which is mediated by monocytic–

microglial cells.’ No significant toxicity, side effects

or autoimmune responses have been observed

in the animal studies. This raises the exciting

possibility that immunization with AN-1792

can ultimately be used as a treatment and per-

haps also as a prophylactic measure against AD.

Eric Lieber, head of strategic planning at Elan,

says the company will now submit an investi-

gational new drug (IND) application with the FDA.

Phase I clinical studies designed to assess the

safety profile of the vaccine in patients with AD

will be performed before the end of this year,

subject to FDA approval. Within 12 months, the

company hopes to commence trials to assess

drug efficacy. If all goes well, they expect to be

applying for marketing authorization in the USA

and Europe within four to six years.

Reference1 Schenk, D. et al. (1999) Nature 400, 8 July, 173–177

Further readingHull, M. et al. (1999) Drug Discovery Today 4, 275–282

What are the unmet needs in cancer therapy

and how are they being addressed? This was the

theme for the first day of the SMi Therapeutic

Cancer Drugs II conference (8 June 1999, London,

UK). Cancer is one of the deadliest killers within

Western populations and the pharmaceutical

industry is constantly under pressure to in-

novate and invest in novel research to ad-

dress the needs of cancer patients1,2. The open-

ing presentation by David Snary [Research and

Development Manager, Imperial Cancer Re-

search Technology (ICRT, London, UK)] outlined

the role of independent academic research in

the discovery and development of new thera-

peutics. The main thrust of the presentation

centred on the so-called ‘development gap’

that exists between academia and industry.

There is a different focus for each group in

terms of aim and final outcomes from research

projects. A feature of academic research is origin-

ality combined with serendipitous research

focused on the publication of work, whereas

industry is characterized by product develop-

ment through to marketing and regulatory re-

quirements for the generation of profitable

therapies.

Development gapSnary suggested that there is a need to create

better links between academic establishments

and industry to facilitate identification and de-

velopment of new opportunities. The benefits

could flow in both directions, support for basic

academic research programmes and the cre-

ation of a link between this basic research and

its application within a clinical environment.

Snary continued with specific examples

of the successes that ICRT has achieved, dis-

cussing the research collaboration with London-

based biotechnology company, Antisoma, in the

update news PSTT Vol. 2, No. 9 September 1999

1461-5347/99/$ – see front matter ©1999 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(99)00191-1348

Defining unmet needs in cancer therapyDavid Andrews, 21 Colin Court, Woodfield Avenue, Streatham, UK SW16 1LJ, tel: 144 181 677 8781

Adrian Smith, Pharmaceutical Science & Technology Today, tel: 144 1223 315961, fax: 144 1223 464430, e-mail: pstt@current-trends.com

development of novel cancer vaccines. To con-

clude, Snary stated that continued communi-

cation between academia and industry should

be encouraged and developed to facilitate

discovery and development of new therapies

and/or diagnostics that cannot be achieved

through mainstream industry research.

Building an oncology portfolioSarah Hatty, formerly Head of European Oncology

for Eli Lilly (UK), covered the issues that sur-

round the reporting of oncology clinical trials.

The main issues covered:

• response rates to drugs – why is there so

much variability in clinical trials?

• toxicity assessments – is it the drug or the

disease that causes confusion?

• what are the trial endpoints – what are the

criteria and when are they satisfied?

Hatty concluded that, with the shift towards

greater specificity and reduced toxicity, there is

a greater need for a globally accepted (by the

investigators, industry and regulatory bodies)

response criteria. She also pointed out that the

array of new classes of compounds in current

development will require new criteria for re-

porting, which will again require close collabo-

rations between the three bodies mentioned.

This need for co-operation and collaboration

with regulatory authorities was echoed by Iain

Sim, Global Product Leader for Xeloda (Hoffman-

LaRoche). He discussed the need for new and

effective treatments against cancer. Using the

development of Xeloda as his example, Sim out-

lined Roche’s regulatory strategy in the treat-

ments for breast and colorectal cancers and the

extension of the life cycle of the drug through

development for new indications. His recom-

mendation in the development of new drugs

was to understand the regulatory procedures

and maintain close contact with regulatory

bodies during the development phase.

Anthony Walker, CEO at Onyvax, provided an

in-depth look at cancer vaccines and their high

market potential, with the possibility of treating

a broad range of cancers. Using his company’s

prostate cancer vaccine as a driving example,

Walker explained how early clinical evaluation

coupled with rational design methods was di-

recting their research for the development of

new vaccine candidates and new approaches.

Research, development, commercialization and communicationDay two, chaired by Roy Drucker [Technomark

Consulting Services Ltd (London, UK)], opened

with a presentation from Elaine Farmery (Marie

Curie Cancer Care, UK) that detailed research

and patient requirements. Farmery stressed the

importance of effective communication be-

tween work at a research level and the patient,

citing a need for information that is distributed

‘as and when’ and that is reliable, clear and edu-

cates in the event that associated side effects

may negate any benefits.

Farmery concluded that, in the future, cancer

patients can expect earlier diagnosis, increased

levels of screening, genetic manipulation, to live

longer with the diagnosis, increased specialist

treatment and a holistic approach. However,

she sees effective, involved communication as

key to these developments, suggesting that

pharmaceutical manufacturers would be well

advised to take heed of an ancient Chinese

proverb: tell me – I forget; show me – I remember;

involve me – I understand.

DevelopmentRifat Pamukcu (Cell Pathways, Inc.) discussed

the development and commercialization of can-

cer drugs, making particular reference to selec-

tive apoptotic anti-neoplastic drugs (SAANDS) –

and Exisulind in particular – as agents for cancer

prevention. According to Pamukcu, 28 million

people in the USA currently have colonic polyps.

Of this figure, approximately 10% are high-rate

formers who may benefit from chemopreven-

tion, and thus Pamukcu suggested that the po-

tential market for cancer prevention could far

outweigh the cancer treatment market.

Pamukcu believes that SAANDS may form

the basis for future therapies in this market.

These drugs reportedly feature a novel mecha-

nism of action through selective induction of

apoptosis via phosphodiesterase inhibition. In

addition, it was reported that the compounds

lack the toxicities associated with hormonal and

chemotherapeutic agents, and offer activity in a

wide range of cancer cell lines and animal mod-

els. In terms of Exisulind, Pamukcu disclosed

that the commercialization strategy for this

agent will involve the pursuit of accelerated

clinical development, and the application of a

novel pathway for the identification of ad-

ditional target tissues and agents for cancer

therapy and chemoprevention. Furthermore,

it is hoped that the product rights will be

retained in order to maximize value, that prod-

ucts will be commercialized directly to focused

physician groups, and strategic collaborations

will be developed for selected indications and

markets.

Emerging and existing therapiesBjorn Nordenvall and David Sherris (OXiGENE

Inc., Boston, MA, USA) provided an interesting

insight into their work in developing a new

class of anti-cancer therapies, anti-tumour vas-

cular targeting agents. These agents feature a

similar action to angiogenesis inhibitors in that

they target a tumour’s network of blood vessels,

which transport vital nutrients for growth and

survival (its ‘life support system’). However, un-

like angiogenesis inhibitors, which have been

demonstrated to only stop the formation and

growth of new blood vessels, anti-tumour vas-

cular targeting agents concentrate on targeting

and destroying blood vessels in existing tu-

mours, which can lead to tumour shrinkage and

eventual removal.

According to OXiGENE, CA4P, the company’s

anti-tumour vascular targeting agent, has

demonstrated a capability to destroy tumour-

related vessels in animals, leaving healthy tissue

intact. In addition, whereas traditional therapies

attack each cell on an individual basis, CA4P

destroys thousands of cancer cells at once by

killing the life support system, and preclinical

studies have shown that the agent enhances

radiation therapies by significantly reducing

blood flow within tumours and allows for a de-

crease in the radiation dose required to induce

local tumour control.

According to Nordenvall and Sherris, in

preclinical studies a single dose of CA4P de-

stroyed 95% of solid tumour cells, and the

company is currently performing an evaluation

of this therapy in three Phase I/II clinical trials

PSTT Vol. 2, No. 9 September 1999 update conferences

349

for patients with advanced stage cancers.

Furthermore, although much of the focus is on

use of the agent as a stand-alone therapy, it is

also thought that CA4P may be used in combi-

nation with traditional treatments, such as radi-

ation and chemotherapy, and OXiGENE plans to

perform clinical studies in this area.

R. Russell Martin (Hybridon) outlined the

current status and advantages of antisense

drugs for cancer, and described promising re-

sults of clinical trials with antisense oligonu-

cleotides. According to Martin, the safety pro-

file supports combination with a wide range of

other antitumour therapies, and early results

with advanced-generation oligonucleotides are

confirming the benefits of improved stability,

enhanced safety profile, and flexible dosing.

Mitchel Sayare (Immunogen) detailed the

benefits to be found in the application of tumour-

activated prodrugs (TAPs), citing high specificity,

minimal side effects, therapeutic-activation by

target cells only, high toxicity at the tumour site

and favourable levels of potency and safety.

Sayare revealed that TAP lead compounds are

currently nearing the clinic and will offer a po-

tent and specific approach with broad appli-

cation and should provide multiple partnering

opportunities.

In the final paper, Donald L. Drakeman

(Medarex) presented global survey results, con-

ducted in 1996 by the Pharmaceutical Research

and Manufacturers of America and reported in

Biotechnology Medicines in Development, re-

lating to the use of antibodies as therapeutics.

Drakeman described the initiation of new cancer

products in the Antibody Age, and, as with each of

the day’s proceedings, highlighted the wealth of

current activity in attempts to discover, develop,

market and deliver effective cancer therapies.

The resounding conclusion to the conference

was that, in addition to strategic collaborations

between pharmaceutical companies, patient

consultation and involvement is key to reducing

drug development times and increasing the

success of future cancer treatments.

Further reading1 White, C.A. et al. (1999) Pharm. Sci.Technol.Today

2, 95–102

2 Pitts, A.E. and Corey, D.R. (1999) Drug Discovery

Today 4, 155–163

We are all excited, and maybe a little fearful,

about the challenges and opportunities facing

pharmaceutical R&D. PricewaterhouseCoopers

(PwC) highlighted these challenges in its report,

Pharma 2005 – An Industrial Revolution in R&D

(Ref. 1). At the recent Pharma Directions ’99

event (2–4 June 1999, Barcelona, Spain) held in

association with PwC, several key issues emerged.

• Innovation deficit and productivity

• Proliferation of information, data handling

and IT

• Advanced drug discovery technologies

• Pharmacogenetic profiling of populations

• Personalization of healthcare technologies

• Ever-decreasing market exclusivity

• Outsourcing and collaboration

• Pricing transparency

• Customer value

Companies are focusing on these issues and

know that they must find solutions or be fed

into the takeover machine. However, many con-

sider that they still take only a short-term view.

One of the most thought-provoking pres-

entations of the event was given by Jonathan

Peck of the Institute for Alternative Futures

(Alexandria, VA, USA). Peck designs and directs

research programs in the international pharma-

ceutical industry, forecasting markets, R&D,

finance and manufacturing. Peck took this

opportunity to look into the effects that the

man-in-the-street will have on the industry to

2005 and beyond.

Power of market expectationsPeck focused on the end-users as a key determi-

nant of the industry’s future, in terms of success

and the way in which it will operate. He marked

the transition points of the second half of the

20th century – first, market acceptance (post-

penicillin), then market caution (thalidomide era)

followed by market hopes (antiviral therapies)

and, finally, market expectations (characterized

by market reaction to Viagra). The market now

has real expectations from the value of medi-

cines across the therapeutic spectrum of cure,

treatment, prevention and enhancement.

Peck highlights how the future for the industry

is therefore bound-up in the interplay of these ex-

pectations against a backdrop of revolutionary

technologies producing better treatments tar-

geted to specific user-groups, increasing focus on

outcomes and the advent of e-economics. Prog-

nostics become a real option: people will be able

to obtain probability statements on the basis of

their genetic profile. The market will drive new

healthcare requirements: the demand for and

ability to provide personalized care will become a

reality. Peck predicts that advances in technol-

ogies such as micro-electro-mechanical systems

(MEMS) will be hugely enabling in healthcare

for example when used, say, in a smart T-shirt

able to monitor functions and well-being. In

fact, smart devices and smart homes could

largely replace the hospital.

Drivers for changeAvailability of information will be a major driver

for changes in the healthcare market. The inter-

ested patient is now able to glean more detail

about their specific complaint over the Internet

update conferences PSTT Vol. 2, No. 9 September 1999

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Cutting a deal with the baby boomersDavid Hughes, Pharmaceutical Science & Technology Today, tel: 144 1223 315961, fax: 144 1223 464430, e-mail: pstt@current-trends.com