|
Companies
Sprint toward Alzheimer's Disease-Modifying Drug
By
Lucy
Sannes, Ph.D., Sannes
& Associates
December 7, 2006
The
market opportunity is untapped, and the time is now. The
race is on for a treatment that can modify Alzheimer’s
disease (AD). As the average age of the
US
population rises, AD represents an ever-growing healthcare
crisis. It is a devastating disease without a
cure, and the economic impact to society is huge:
According to the Alzheimer’s Association and the
National Institute on Aging, 4.5 million Americans have AD
and the cost of caring for these patients is at least $100
billion each year. Compounding the problem is the fact
that although currently approved drugs can alleviate
symptoms and slow progression of AD, they do not treat its
underlying cause.
AD is the
leading cause of dementia. As the population ages, the
number of Americans with AD may grow to as many as 16
million by 2050, according to the Alzheimer’s
Association. The
National Institute on Aging estimates that currently, 5%
of people aged 65 to 74 years have AD, and nearly half of
those 85 years of age or older may have the disease.
Notably, preliminary
reports from a recent Mayo Clinic study suggest that
approximately 12% of people over the age of 70 years have
mild cognitive impairment (MCI). This fact further fuels
the need for an AD treatment, as people with MCI are three
to four times more likely to develop AD than those
without.
The
market for AD drug therapy in the
US
, Europe, and
Japan
exceeded $3 billion in 2005, according to Millennium
Research Group. By 2009, approximately 10 million people
in this global market will suffer from Alzheimer’s
disease.
The
Culprits: Problematic Protein Structures
In the
brain, the hallmark characteristics of AD are amyloid
plaques and neurofibrillary tangles. Amyloid plaques are
clumps of beta-amyloid, a protein fragment that is
produced by abnormal processing of the amyloid precursor
protein (APP). Beta-amyloid has also been called amyloid
beta or Aβ.
A major component of the neurofibrillary tangles is the
protein tau. Development of these abnormal structures in
the brain eventually results in disruptions in the
transmissions between nerve cells (neurons) and death of
the neuron.
FDA-Approved Drugs to Alleviate
Alzheimer’s Symptoms
The Food
and Drug Administration (FDA) has approved five drugs for
treatment of AD (see Table 1). All of these drugs treat
cognitive symptoms of the disease and can slow its
progression. However, they do not treat the underlying
cause of the disease. The first four drugs to reach the
market were cholinesterase inhibitors (also called
acetylcholinesterase inhibitors). These drugs block
breakdown of the chemical messenger acetylcholine in the
brain. Acetylcholine is thought to be important in memory
and cognitive function, and the amount of acetylcholine
produced by the brain decreases as AD progresses. Cognex,
the first cholinesterase inhibitor to reach the market, is
rarely prescribed now due to side effects. The leading
product for treatment of AD is Aricept (donepezil), which
was originally discovered and developed by Eisai (
Japan
), and is marketed by both Eisai and Pfizer. All of the
acetylcholinesterase inhibitors were initially developed
for treatment of mild to moderate AD. However, in October
2006, the FDA approved Aricept for treatment of severe AD,
thus expanding its approved indications.
The
newest drug to reach the market for treatment of
Alzheimer’s disease is memantine, which is marketed in
the
US
by Forest Laboratories under the brand name Namenda.
Forest licensed memantine from Merz Pharmaceutical GmbH.
Merz; its other licensees market memantine outside of the
US
under different brand names. Memantine is an N-methyl-D-aspartate
(NMDA) receptor antagonist. It is currently approved by
the FDA for treatment of moderate to severe AD.
Forest
is seeking to expand the approved indication for Namenda.
In November 2004,
Forest
announced that the FDA had accepted a supplemental New
Drug Application to expand the indication for Namenda to
include treatment of mild AD. Use of memantine for
treatment of AD patients is growing. However, like other
AD drugs available today, memantine may help relieve
symptoms, but does not treat the underlying cause of the
disease.
Companies
Rise to Meet Urgent Need
As
noted previously, AD is a large market with significant
unmet needs. Numerous companies have research or
clinical programs to develop new therapies for treatment
of AD. According
to Navigant Consulting, a new crop of drugs in development
aimed at preventing and combating the characteristic
buildup in the brain of amyloid plaques is expected to
come to market by 2011.
Selected
examples of drug candidates in Phase II or later clinical
development are shown in Table 2. As demonstrated by the
product candidates in this table, pharmaceutical and
biopharmaceutical companies are pursuing a wide range of
approaches and targets in the effort to develop new
treatments for AD.
Several
of the emerging therapies listed in Table 2 are based on
disease-modifying approaches to prevent or reduce buildup
of the amyloid plaques. Potential mechanisms
include inhibiting beta-secretase or gamma-secretase
(thus blocking cleavage of APP), blocking aggregation of
beta-amyloid, and other approaches to reduce buildup of
beta-amyloid and the amyloid plaques. Many companies are
developing secretase inhibitors, but most of the secretase
inhibitor programs are in only early-stage development,
and therefore are not included in Table 2. Two of the more
advanced disease-modifying agents that target buildup of
amyloid plaques are Myriad Genetics’ Flurizan and
Neurochem’s Alzhemed, both of which are being evaluated
in Phase III clinical trials.
Myriad
Genetics reports that Flurizan is a selective amyloid-lowering
agent (SALA) that reduces levels of the peptide amyloid
beta 43 in cultured human cells and in animal models.
Results of a completed Phase II follow-on study of
Flurizan in patients with mild AD were presented in July
2006 at the International Conference on Alzheimer’s
Disease and Related Disorders. According to Myriad
Genetics, results from this study reportedly supported the
hypothesis that Flurizan may have disease-modifying
effects, and that the longer patients with mild AD are
treated with Flurizan, the more slowly their disease will
progress. Flurizan is currently being evaluated in two
Phase III clinical trials. Act-Earli-AD Global (A Clinical
Trial to Evaluate Aß42 Reduction
for Limiting the Impact of Alzheimer’s
Disease) is a global study that includes patients
in the
United States
and several European countries. This study, which is
currently enrolling patients, will include approximately
800 patients with mild AD who will be divided into two
study arms (treatment with 800 mg Flurizan twice daily or
placebo). The primary objective of the study, scheduled to
last 18 months, will be evaluation of changes in cognition
and activities of daily living.
A second
study, called
Act-Earli-AD
US
, is being conducted in the
United States
only and is fully enrolled. This is also a double-blind,
placebo-controlled study in which patients with mild AD
receive either 800 mg Flurizan twice daily or placebo for
18 months.
Neurochem
reports that Alzhemed is thought to reduce deposition of
amyloid by binding to the Aß (also known as beta-amyloid)
peptide. Phase II results
for Alzhemed in patients with mild to moderate AD were
published in the November 28, 2006 issue of Neurology.
Neurochem describes positive results in that Alzhemed was
safe, tolerated, and reduced levels of amyloid beta 42 in
the cerebrospinal fluid of patients with AD.
Alzhemed
is currently being evaluated in two Phase III clinical
trials. The company’s North American trial (in the
United States
and
Canada
) is a randomized, double-blind, placebo-controlled study in
1,052 patients with mild to moderate AD. Patients are
being treated for 18 months. Following completion of the
study, patients are eligible to receive Alzhemed in an
open-label extension study. Neurochem reports that this
study is scheduled for completion in January 2007.
A second
Phase III trial of Alzhemed was initiated in Europe in
September 2005. Neurochem expects to include 930 patients
with mild to moderate AD in this study.
The
current market opportunity for drugs to treat AD is large,
and this market is expected
to grow even more in the future. As demonstrated by
the information in Table 1, current
sales of drugs to treat AD have already exceeded $2
billion per year. The eventual success of emerging
drugs for treatment of AD, including disease-modifying
drugs such as Flurizan and Alzhemed, could ultimately
depend on the clinical performance of these drugs.
However, should such emerging therapies prove to be
successful in the clinic, they have the potential to
significantly penetrate this large and growing market.
For
further reading:
Click
here
for more on Pfizer/TransTech’s potentially
disease-modifying candidate for Alzheimer’s disease.
To
read more about diagnostics for Alzheimer’s disease and
the importance of early detection, click
here.
Table
1: FDA-Approved Drugs for Treatment of AD
|
Company
(Drug
category appears in italics)
|
Product
Name (generic)
|
Year of Initial FDA Approval
|
Approved
Indication(s) and Comments
|
2005
Worldwide Sales
|
Acetylcholinesterase
Inhibitors
|
|
Eisai
and Pfizer
|
Aricept
and Aricept ODT (donepezil)
|
1996
|
•For
treatment of dementia of the Alzheimer’s type.
Efficacy has been demonstrated in patients with mild
to moderate AD, as well as in patients with severe
AD.
•Originally
discovered and developed by Eisai. Aricept is
co-promoted by Pfizer and Eisai in the
US
and several other countries. Pfizer has an exclusive
license to market Aricept in certain countries.
|
Reported
by Pfizer: Some revenues reported separately ($346 million) and others included in total for
Alliance
revenue (which is $1.362 billion and includes other
drugs).
Reported
by Eisai: Global product sales (Eisai territory
sales) of 196.5 billion Yen (approximately $1.7
billion) for fiscal 2006 (ended 3/31/06).
|
|
Novartis
|
Exelon
(rivastigmine)
|
2000
|
•For
treatment of mild to moderate dementia of the
Alzheimer’s type, and for treatment of mild to
moderate dementia associated with Parkinson’s
disease.
|
$467
million
|
|
Ortho-McNeil
Neurologics
(Part
of Johnson & Johnson)
|
Razadyne
(galantamine)
|
2001
|
•For
treatment of mild to moderate dementia of the
Alzheimer’s type.
•Originally
sold under the trade name Reminyl.
|
Not
Available
|
|
Sciele
Pharma
(Formerly
First Horizon Pharmaceutical)
|
Cognex
(tacrine)
|
1993
|
•For
treatment of mild to moderate dementia of the
Alzheimer’s type.
•Originally
developed by Warner-Lambert (which has since been
acquired by Pfizer).
|
Not
Available
|
N-methyl-D-aspartate
(NMDA) Receptor Antagonist
|
|
Forest
Laboratories
|
Namenda
(memantine)
|
2003
|
•For
treatment of moderate to severe dementia of the
Alzheimer’s type.
•Forest
Laboratories licensed US rights to memantine from
Merz Pharmaceuticals GmbH.
•Merz
and its partners market memantine outside the
US
under different brand names.
|
Reported
by
Forest
: US-only sales were $508 million for fiscal 2006
(ended 3/31/06); compared with $333 million for
fiscal 2005.
Reported
by Merz in 2004/2005 Annual Report: Total sales (Merz
and license holders) were $600 million for
2004/2005.
|
Source:
Sannes & Associates, Inc.
Table
2: Selected
Companies with Late-Stage Candidates for Treatment of AD
|
Company
(Drug category
appears in italics)
|
Product/Technology
|
Status
|
Comments
|
|
Disease-Modifying
Agents Targeting Amyloid Plaques
|
|
Eli
Lilly
|
LY2062430
|
Phase
II
|
•Reportedly
may influence beta-amyloid production.
|
|
Eli
Lilly
|
LY450139
|
Phase
II
|
•Gamma
secretase inhibitor.
•For
mild to moderate AD.
|
|
Myriad
Genetics
|
Flurizan
(MPC-7869)
|
Phase
III
|
•Selective
amyloid-lowering agent (SALA) that reduces levels of
the Aβ 42 peptide in cultured human cells and in animal models.
•Being
evaluated in two Phase III trials in patients with
mild AD.
|
|
Neurochem
(
Canada
)
|
Alzhemed
(tramiprosate)
(3-amino-1-propanesulfonic
acid [3APS])
|
Phase
III
|
•Binds
to Aβ
peptide
and maintains this peptide in a non-fibrillar form.
|
|
Prana
Biotechnology (
Australia
)
|
PBT-2
|
10/06
– Approved to start Phase IIa in
Sweden
|
•Reduces
levels of Aβ
protein.
•For
early AD.
|
|
TorreyPines
Therapeutics
|
phenserine
|
Phase
III
(Did
not achieve statistical significance over placebo in
Phase III trial where it was evaluated for
improvement in memory and cognition.)
|
•Dual
mechanism of action: Acetylcholinesterase inhibition
and lowering levels of Aβ
42 peptide.
•For
treatment of mild to moderate AD.
•Acquired
through a reverse merger with Axonyx.
•Licensed
to Daewoong, which has rights for
South Korea
.
|
|
TransTech
Pharma
|
TTP488
|
Phase
II
|
•Small
molecule.
•Reduces
amyloid burden.
|
|
Wyeth
and Elan
|
bapineuzumab
(AAB-001)
|
Phase
II
|
•Humanized
monoclonal antibody to Aβ;
designed to bind to and clear Aβ
peptide.
•Passive
immunization approach.
|
|
Wyeth
and Elan
|
AAC-001
|
Phase
II
(Reported
by Elan)
|
•Immunoconjugate.
•Aβ-related
active immunization approach.
|
|
Other
Agents in Development for AD
|
|
Accera
|
Ketasyn
(AC-1202)
|
Phase
II
|
•First-in-class
therapeutic agent that Accera reports addresses the
energy deficit observed in the brains of AD
patients.
•Phase
IIb trial for AD complete. Accera expects to have
results available by end of 2006, and expects that
results of a six-month open-label extension will be
available during the first quarter of 2007.
•Start
of Phase II trial for age-associated memory
impairment announced August 2006.
|
|
AstraZeneca
|
AZD3480
|
Phase
II
|
•Neuronal
nicotinic receptor agonist.
•For
cognitive disorders/AD.
•12/05:
Agreement with Targacept granted AstraZeneca rights
to Targacept’s TC-1734 (now AZD3480).
|
|
Cortex
Pharmaceuticals
|
CX717
|
Phase
II: Released from clinical hold 10/06
|
•AMPAKINE
compound—AMPAKINE drugs increase the activity of
the AMPA receptor.
|
|
Dainippon
Sumitomo
|
AC-3933
|
Phase
II
(US)
Phase
I (
Japan
)
|
•Partial
inverse agonist of benzodiazepine receptors;
reportedly activates cholinergic neurons by
enhancing release of acetylcholine, and also
stimulates glutaminergic neurons.
•Being
developed for treatment of dementia.
•Phase
II trial in US for treatment of mild to moderate AD;
sponsored by Dainippon Sumitomo Pharma
America
.
|
|
Debiopharm
|
Debio-9902
SR
(ZT-1 SR)
|
Phase
II
|
•Acetylcholinesterase
inhibitor.
|
|
Forest
Laboratories
|
neramexane
|
Phase
III
|
•NMDA
receptor antagonist for moderate to severe AD.
•Licensed
from Merz.
|
|
GlaxoSmithKline
|
rosiglitazone
XR (extended-release tablets)
|
Phase
III (AD)
(Avandia
[rosiglitazone] is on the market for diabetes.)
|
•Peroxisome
proliferator-activated receptor (PPAR) gamma
agonist.
•Rosiglitazone
XR is in Phase III development for mild to moderate
AD. It is also being evaluated in clinical trials
for rheumatoid arthritis.
•Avandia
(rosiglitazone) is FDA approved for use as an
adjunct to diet and exercise to improve glycemic
control in patients with type 2 diabetes mellitus.
Avandia may be used either as a monotherapy or in
combination with sulfonylurea, metformin, insulin,
or sulfonylurea plus metformin.
|
|
Medivation
|
Dimebon
|
Phase
II
|
•Oral
drug that has been on the market since 1983 for
treatment of allergic rhinitis and allergic
dermatitis.
•In
Phase II for AD and in preclinical development for
Huntington’s disease.
•Has
a potential neuroprotective activity, e.g., inhibits
brain cell death.
|
|
Memory
Pharmaceuticals
|
MEM
1003
|
Phase
IIa
|
•L-type
calcium-channel modulator.
•In
Phase IIa trials for AD and bipolar disorder.
|
|
Memory
Pharmaceuticals
|
MEM
3454
|
Pre-Phase
IIa
|
•Nicotinic
alpha-7 agonist.
•Corporate
partner is Roche, which has an option to license MEM
3454.
|
|
Merck
|
MK-0952
|
Phase
I (Phase II planned)
|
•Phosphodiesterase
IV (PDE4) inhibitor for mild to moderate AD.
|
|
Neuro-Hitech
|
Huperzine
A
(oral formulation)
|
Phase
II
|
•Alkyloid
medicine isolated from the plant Huperzia
serrata.
•In
Phase II for AD, in Phase I for neuroprotection
against nerve gas, and in preclinical development
for myasthenia gravis.
•Mechanisms
of action reportedly include acetylcholinesterase
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