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Emerging
HIV Therapies
Part
1: Emerging Therapies That Do Not Target HIV Reverse
Transcriptase or HIV Protease
By
Lucy
Sannes, Ph.D.
Sannes
& Associates, Inc.
October 4, 2006
Up to 20%
of HIV-diagnosed individuals show resistance to at least
one class of current anti-HIV drugs, making the market
rife with opportunity for treatments that work
differently. Combined with the significant side effects
associated with current therapies, there is an urgent need
for new classes of anti-HIV drugs.
The potential payoff is tantalizing: HIV treatments
netted over $7 billion in sales last year.
HIV
infection continues to be a major problem worldwide.
The Centers for Disease Control and Prevention
estimates that over 1 million individuals were living with
HIV/AIDS in the United States
in 2003. On a
global basis, the World Health Organization (WHO)
estimates that 39 million people worldwide were living
with HIV in 2005.
More than
20 compounds and an even greater number of formulations
are available for the treatment of HIV-infected persons.
With one exception, all of the FDA-approved
antiretroviral drugs are members of three classes of
drugs: the nucleoside reverse transcriptase inhibitors (NRTIs),
the non-nucleoside reverse transcriptase inhibitors (NNRTIs),
or the protease inhibitors.
These drugs are typically given in regimens of
three or more drugs, a practice which is referred to as
highly active antiretroviral therapy (HAART).
While these drugs cannot cure patients with HIV
infection, they can significantly suppress HIV
replication. Ongoing
activities to develop new drugs that are members of these
three classes of drugs will be discussed in Part 2 of this
article.
According
to a recent Espicom report, the
largest segment of the antiviral market is derived from
the treatment of HIV, with reported sales of around $7
billion in 2005. The
US
market accounts for around 60%, equating to over $5
billion, while in Europe,
France
has the largest market value with revenues of around $600
million. HIV-reverse transcriptase inhibitors were among
the top 20 leading therapeutic drug classes (based on 2005
US
sales), generating global sales of $5 billion.
While
development of the currently available HIV therapies
represented a significant advance for treatment of
HIV-infected individuals, these drugs have limitations.
The two major ones are that they can cause
significant side effects and HIV can develop resistance to
these drugs.
HIV
Drug Resistance Is a Major Concern
Last
year, the WHO reported that wherever
HIV therapy is available, drug resistance will occur to
some degree. According to the WHO article, in
industrialized countries, where antiretroviral treatment
has been widely accessible for almost a decade, small
studies have suggested that between 5% and 20% of
individuals diagnosed with HIV have become resistant to at
least one class of anti-HIV drugs.
Results
from a survey commissioned by the
American
Academy
of HIV Medicine, released in July, highlight the major
issue of HIV drug resistance in the US, reporting that more than 90% of physicians surveyed are
“extremely” or “very” concerned about the
issue.
Fusion
Inhibitors Are First New Class to Hit Market
The
newest class of drug to reach the market for the treatment
of HIV is the fusion inhibitors.
The only marketed fusion inhibitor is Roche’s
Fuzeon (enfuvirtide), which received FDA approval in March
2003. Fuzeon
was developed by Trimeris Pharmaceuticals and Roche.
Fuzeon is an injectable drug; hence, an oral,
small-molecule fusion inhibitor would provide a new
therapeutic option.
Fuzeon
inhibits the fusion of HIV to CD4-positive cells by
binding to the gp41 subunit of the viral envelope protein,
thus preventing conformational changes that are required
for fusion of HIV and the cell membrane.
Fuzeon is FDA approved for treatment of HIV-1
infection in treatment-experienced patients who have
exhibited evidence of HIV-1 replication despite their
ongoing antiretroviral therapy.
Fuzeon is not used as part of the initial HAART
therapy in treatment-naïve patients.
Fuzeon must be injected twice per day, and in Phase
III clinical trials, 98% of patients had at least one
local injection-site reaction.
Due to this problem, patients taking Fuzeon are
told that each injection should be given at a different
site than the previous one, and that injections should
only be made at sites where there is no prior reaction.
Another
of Fuzeon’s limitations is that HIV can develop
resistance to it, as it can to other available HIV drugs. These
limitations have served to limit Fuzeon’s sales.
For 2005, Roche reported Fuzeon sales of 259
million Swiss francs (approximately $210 million).
However, use of Fuzeon is increasing: Its 2005
sales represented a 53% increase over its 2004 sales.
Fusion
inhibitors such as Fuzeon are members of a broader group
of emerging HIV therapies known as viral-entry inhibitors.
All viral-entry inhibitors act by blocking the
entry of HIV into the cell, but they can work by a number
of different mechanisms.
These include: blocking the attachment of HIV to
the cell, blocking receptors (such as CCR5 or CXCR4) that
are required for viral entry, or blocking fusion of HIV to
the cell membrane. Several
viral-entry inhibitors are in clinical development (see
accompanying table [below]), but this is proving to be a
difficult field.
For
example, Trimeris and Roche were developing a
second-generation HIV fusion inhibitor (T-1249) that binds
to a different region of HIV than does Fuzeon.
As a result, T-1249 was expected to be effective
against Fuzeon-resistant HIV.
However, in January 2004 the two companies put
clinical development of T-1249 on hold, citing challenges
in achieving the desired technical profile of the
formulation. According to Trimeris’ Web site, T-1249’s
safety, efficacy, and tolerability were in no way related
to the decision. They are instead developing new HIV
fusion inhibitors, which are still in preclinical
development.
Most
viral-entry inhibitors in development today are in Phase
II or earlier stages of development.
The most advanced viral-entry inhibitor is
Pfizer’s maraviroc, a CCR5 receptor antagonist that is
in Phase III development.
In July 2006, while reporting the company’s
second-quarter results, Pfizer indicated that it is
targeting an NDA submission for maraviroc for treatment of
treatment-experienced, HIV-infected patients by the end of
2006.
The HIV
integrase inhibitors are another emerging class of HIV
therapies. An
important step in the HIV life cycle is integration of
viral DNA into the host cell’s DNA.
Integrase inhibitors block the enzyme responsible
for this integration.
Several integrase inhibitors are in development
(see table). The
most advanced integrase inhibitor is Merck’s MK-0518,
which is in Phase III clinical development.
MK-0518 is being evaluated in both treatment-naïve
patients as well as in patients who have failed current
antiretroviral therapy.
Merck’s
Integrase Inhibitor Shows Highly Promising Efficacy
In August
2006, promising interim (24-week) data was reported from
an ongoing Phase II, dose-ranging trial of MK-0518 in
treatment-naïve, HIV-infected patients.
In this study, patients received either 1) MK-0518
in combination with Viread (tenofovir) and Epivir (lamivudine),
or 2) Sustiva (efavirenz) in combination with Viread and
Epivir. After
24 weeks, 85% to 95% of patients taking the MK-0518-based
regimen had achieved reductions in HIV viral load to less
than 50 copies/mL, while 92% of patients taking Sustiva
had achieved this reduction.
Thus, MK-0518 appears to be equivalent to Sustiva
in this treatment regimen.
In addition, MK-0518 was reportedly well tolerated.
If MK-0518 is eventually approved for both the
treatment-naïve and treatment-experienced patient
populations, its potential market opportunity will be
significantly larger than for drugs (such as Fuzeon) that
are approved only for treatment-experienced patients who
are failing therapy. In
August 2006, Merck announced a worldwide, expanded early
access program for patients who have either limited or no
treatment options, making MK-0518 available to them.
Another
emerging class of HIV therapies is the HIV maturation
inhibitors, which inhibit the final step in the processing
of the HIV gag protein.
Only one maturation inhibitor is in clinical
development at this time--Panacos Pharmaceuticals’
bevirimat (PA-457), which is in Phase II clinical trials.
Panacos has completed seven clinical studies of
bevirimat in over 300 subjects, showing significant
reductions in viral load in HIV-infected subjects and a
promising safety profile.
Much
Work Remains
Many
additional emerging HIV therapies have also reached
clinical development, several examples of which are presented in the table below.
Many of these are based on either immunotherapy
(i.e., stimulating the immune system) or gene therapy.
It appears that none of these other emerging HIV
therapies have reached Phase III clinical development.
There is a
significant need for HIV therapies that operate by novel
mechanisms of action, as more patients develop drug
resistance and exhaust the current arsenal of anti-HIV
treatments. The successful development of these novel
therapies is proving to be a challenge and is taking
considerable time. Only
two HIV therapies based on novel mechanisms of action
appear to be in Phase III development at this time.
However, due to the limitations of currently
available anti-HIV drugs, the potential opportunity for
these emerging therapies is significant if they can
successfully navigate the path to market.
Selected
Emerging HIV Therapies Based on New Mechanisms of Actions
in Clinical Development*
|
Company
|
Product
or Mechanism of Action
|
Status
|
Comments
|
|
HIV
Entry Inhibitors
|
|
AnorMED
|
AMD-070
|
Phase
Ib/IIa
|
•CXCR4
inhibitor
|
|
Bristol-Myers
Squibb
|
HIV
Attachment Inhibitor
|
Exploratory
development (Phase I or II)
|
•For
HIV/AIDS
|
|
Human
Genome Sciences
|
CCR5
mAb
(Human
monoclonal antibody to the CCR5 receptor)
|
Phase
I
|
•Fully
human monoclonal antibody
•Blocks
CCR5-dependent HIV-1 entry into cells, cell-cell
fusion, and viral transmission
|
|
Pfizer
|
maraviroc
(UK-427,857) |
Phase
III
|
•CCR5
receptor antagonist
|
|
Progenics
Pharmaceuticals
|
PRO
140
|
Phase
Ib
|
•Viral-entry
inhibitor – Humanized monoclonal antibody
targeting the CCR5 receptor
|
|
Samaritan
Pharmaceuticals
|
SP-01A
|
Phase
IIb
|
•Oral
viral-entry inhibitor – Targets CXCR4/CCR5 HIV
co-receptors
|
|
Schering-Plough
|
Vicriviroc
|
Phase
II
|
•CCR5
receptor antagonist
|
|
Tanox
|
TNX-355
|
Phase
II
|
•Viral-entry
inhibitor
•Monoclonal
antibody that binds to the CD4 receptor
|
|
Trimeris
and Roche |
T-1249
|
Clinical
development on hold
(Reached
Phase I/II) |
•Second-generation
fusion inhibitor that is active against Fuzeon-resistant
HIV
|
|
Integrase
Inhibitors
|
|
Bristol-Myers
Squibb
|
HIV
Integrase Inhibitor
|
Exploratory
development (Phase I or II)
|
•For
HIV/AIDS
|
|
Gilead
Sciences
|
GS
9137
|
Phase
II
|
•Oral
HIV integrase inhibitor
•Licensed
from Japan
Tobacco in 3/05.
Japan Tobacco retained rights in
Japan.
|
|
GlaxoSmithKline
and Shionogi |
364735
|
Phase
I (US) |
•Oral
HIV integrase inhibitor
•Being
developed by Shionogi-GlaxoSmithKline
Pharmaceuticals LLC
|
|
Merck
|
MK-0518
|
Phase
III
|
•Oral
HIV integrase inhibitor
|
|
Maturation
Inhibitors
|
|
Panacos
Pharmaceuticals
|
bevirimat
(PA-457)
|
Phase
II
|
•Inhibits
the final step in the processing of the HIV gag
protein
|
|
Other
Emerging HIV Therapies
|
|
CytoDyn
|
Cytolin
|
Phase
I/II
|
•Targeted
immune therapy for HIV/AIDS
|
|
Enzo
Therapeutics
(Enzo
Biochem)
|
HGTV43
|
Phase
I
|
•Gene
medicine
•Uses
Enzo Biochem’s Stealth Vector, which carries
anti-HIV-1 antisense RNA genes directed against the
genes required for viral replication
|
|
Hemispherx
Biopharma
|
Ampligen
|
Phase
IIb for HIV
Phase
III planned
|
•Double-stranded
RNA drug product
•Immunotherapeutic/antiviral
agent
•Also
being developed for CFIDS/ME (Phase III completed)
and avian flu (preclinical)
|
|
Hemispherx
Biopharma
|
Alferon
Low Dose
Oral (LDO)
(interferon
alfa-n3 [human-leukocyte derived])
|
In
preparation for Phase II for HIV
|
•A
natural interferon
•Potential
therapy for viral diseases
|
|
Hollis-Eden
Pharmaceuticals
|
Immunitin
(HE2000)
|
Phase
I/II and Phase II trials completed
Phase
II/III planned for infectious disease
|
•Immune
regulating hormone (IRH)
•Has
shown activity in Phase II trials for malaria, HIV,
and late-stage AIDS; has shown preclinical benefit
in tuberculosis models
•Company
is seeking partnerships to provide funding for a
Phase II/III trial in infectious disease
|
|
Immune
Response Corp.
|
Remune
|
Phase
II
|
•HIV-1
immunogen – Immune-based therapy for HIV
|
|
Immune
Response Corp.
|
IR103
|
Phase
II
|
•HIV-1
immunogen with Aplivax (an immunostimulatory
oligonucleotide adjuvant developed by Idera
Pharmaceuticals)
|
|
Pharmexa
|
EP1090
|
Phase
I/II
|
•Therapeutic
vaccine against HIV
•Epitope-based
DNA vaccine
|
|
Polymun
Scientific
|
Anti-HIV
monoclonal antibodies
|
Phase
II
|
•Three
neutralizing antibodies for prevention as well as
therapeutic indications
|
|
Sanofi-Pasteur
(Part
of
Sanofi-Aventis)
|
Therapeutic
HIV vaccine
|
Phase
II
|
--
|
|
Virax
Holdings
(
Australia
)
|
VIR201
|
Phase
I/IIa
|
•Immunotherapeutic
for HIV
|
|
Virionyx
(
New Zealand
)
|
HRG214
|
Phase
I complete
Phase
II planned
|
•Polyclonal
caprine antibody against purified lysates of
different HIV strains from multiple types of cells
|
|
VIRxSYS
|
VRX496
|
Phase
II
|
•HIV
lentiviral vector that is created by removing the
disease-causing parts of the virus, and then
inserting a long antisense sequence against the HIV
envelope protein
|
*
Agents that do not target HIV reverse transcriptase or HIV
protease.
Source:
Lucy Sannes, Ph.D.
Copyright
2006, All Rights Reserved. Cambridge Healthtech Institute.
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