Download HIV / AIDS

Biotechnology/Pharmaceuticals
Chrystyna Bedrij
Thomas Finnigan
Scott C. Matchett, CFA
HIV/AIDS Industry
Report – April 2005
MAJOR
DEVELOPMENTS IN THE
TREATMENT OF
HIV / AIDS
The Problems…
…The Solutions?
Griffin Securities, Inc., 17 State Street, New York, NY, 10004 • Member NASD, SIPC • (212) 509-9500
PLEASE REVIEW DISCLOSURES ON PAGE 49 OF THIS RESEARCH REPORT
TABLE OF CONTENTS
1.
EXECUTIVE SUMMARY
2
2.
THE HIV LIFE CYCLE
4
3.
MUTATIONS AND RESISTANCE
6
4.
NEW GOVERNMENT GUIDELINES
7
5.
HIV/AIDS STATISTICS WORLDWIDE
8
6.
ANTIVIRAL DRUGS: NRTIS, NNRTIS, AND PIS
10
6.1 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS / NUCLEOSIDE ANALOGUES / “NUKES” 11
6.2 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)
19
6.3 PROTEASE INHIBITORS (PIS)
23
7.
NEW DIRECTIONS IN TREATMENT
7.1 HIV ENTRY INHIBITORS
7.2 IMMUNE-BASED THERAPIES AND OTHER ADJUNCT APPROACHES
7.3 ALTERNATIVE APPROACHES
8.
VACCINES
28
31
33
36
8.1 VACCINE DEVELOPMENTS
9.
28
38
CONCLUSION
46
DISCLOSURES
49
1
1.
EXECUTIVE SUMMARY
Current research and development for HIV is focused on adjunctive therapy, which when combined
with existing HAART (Highly Active Anti-Retroviral Therapy) regimens reduce side effects, enhance
the efficacy of existing treatments and delay the progression of the HIV virus. The majority of
these therapies are currently in clinical trials in late stage patients, where existing HAART regimens
fail due to a build-up of drug resistance and a worsening of immune response. Choosing a proper
salvage therapy remains a vexing problem in HIV treatment, particularly for patients that have
failed multiple anti-viral drug regimens. It is likely that salvage therapy will become more prominent
going forward as currently treated HIV infected patients develop resistance.
Today, there are approximately 25 AIDS drugs on the market, falling into four general classes:
Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Protease Inhibitors (PIs), Non-Nucleoside
Reverse Transcriptase Inhibitors (NNRTIs); and Fusion Inhibitors. These drugs are usually used in
combinations of three or more to create an effective antiviral therapy. In addition, there are
multiple investigational new drug applications (INDs) that have been submitted to the U.S. Food
and Drug Administration to conduct clinical trials on HIV candidates.
With approximately five million people becoming newly infected with HIV in 2004 combined with the
ability of HIV infected people to live longer than in years past due to better efficacy in novel antiHIV drugs; the market for antiretroviral therapy should continue to grow. In the continued absence
of any “cure” we expect the use of combination or “cocktail” therapy to continue to increase the
overall size of the HIV market in the future. Anti-HIV drug sales were approximately $6 billion in
2003 and this market has the potential to reach $10 -$12 billion by 2007/8. As a fairly immature
market, new drugs and adjunct therapies with novel mechanisms of action or unique resistance
profiles are sorely needed in the fight against HIV. Constant innovation, in terms of efficacy, side
effect profile, and dosing are helping to expand the market.
Although combination therapy has demonstrated the ability to slow resistance development,
resistant mutant strains have been identified to the drugs currently used during the course of
coactive therapy studies, and cross-resistance among many agents has been increasingly
recognized. Even brief periods of non-compliance can reduce or eliminate the ability of coactive
therapy to suppress the virus, and may thus accelerate the development of resistance. Once-daily
therapies will most likely continue to increase in demand in the near future.
GlaxoSmithKline (NYSE: GSK) continues to have the strongest franchise in NRTIs, with
Combivir®, Trizivir® and Epivir® leading the way. GlaxoSmithKline achieved anti-HIV drug sales of
$2.8 billion in 2004, an increase of 4 percent from 2003. GlaxoSmithKline currently has just over
50 percent of the market share in NRTIs. Gilead Sciences (NasdaqNM: GILD) has taken over the
number two spot in the nucleoside reverse transcriptase inhibitor market. This is in large part due to
the success of Viread® which achieved sales of $782 million in 2004, an increase of 38 percent.
Gilead’s new combination drug Truvada® (emtricitabine and tenofovir) should further Gilead’s
market share of antiretroviral therapy. Truvada® also has the potential to compete with
GlaxoSmithKline’s leading product Combivir®. With multiple promising drugs in the pipeline over
the next few years we expect the competition to steadily increase.
Abbott Pharmaceutical’s (NYSE: ABT) Kaletra® is currently the leader among protease
inhibitors. In mid 2003 Kaletra® was leading the way with 32% of new PI subscriptions and 34%
of total PI subscriptions. Protease Inhibitors (PIs) are the second category of antiretroviral drugs on
the market. PIs are extremely powerful but unfortunately they are accompanied by relatively strong
side effects. Many drug companies are currently working to develop drugs that are more potent,
less toxic, and have improved dosing regimens. GlaxoSmithKline/Vertex’s (NYSE: GSK,
NasdaqNM: VRTX) Lexiva® is poised to take a portion of the protease inhibitor market. Its low
pill burden and flexibility in dosing make it very appealing to many patients. Bristol-Myers
Squibb’s (NYSE: BMY) Reyataz® is a very strong contender in the PI market with its high potency
and effectiveness against resistant strains of HIV. Reyataz® achieved sales of $414 million in 2004.
Merck & Co (NYSE: MRK) continues to have a strong share in the Protease Inhibitors market with
its product Crixivan® and drug giant Pfizer (NYSE: PFE) controls a significant share of the market
with its PI drug Viracept®. Pfizer’s share of the market is expected to diminish with the publication
of recent studies comparing Kaletra® and Viracept® where Kaletra® outperformed Viracept® in
safety and efficacy. The Protease Inhibitor market is currently very vulnerable to penetration by
more novel PIs including many that are currently in development.
2
Bristol-Myers Squibb’s (NYSE: BMY) Sustiva® continues to be the market leader in NNRTIs with
year 2004 revenues of $621 million, an increase of 14% from 2003. Sustiva® currently has a
13.8% share of the new prescriptions in the NNRTIs and NRTIs combined and also continues to be
the most prescribed product among PIs and NNRTIs. Sustiva® has 65 percent of the new and total
NNRTI prescriptions. NNRTIs are the third category of currently approved anti-virals medications.
There are only three approved NNRTIs including Viramune® by Boehringer Ingelheim, Sustiva®
by Bristol-Myers Squibb, and Rescriptor® by Pfizer. There are currently many NNRTIs in the
drug pipeline. Capravirine developed by Pfizer’s Agouron Unit and TMC125 developed by
Tibotec are some of the more promising drugs that are poised to enter the market in the near
future. Penetration by NNRTIs into the antiretroviral drug market is difficult because each drug
must also compete with the PIs for the coveted third spot in the triple-drug “cocktail”.
Roche Pharmaceuticals (OTC: RHHBY.PK) and Trimeris, Inc. (Nasdaq: TRMS) are the
leaders in the fourth class of antiretroviral treatment known as fusion inhibitors. Their leading
product, Fuzeon®, had sales of $135 million in 2004. Currently Fuzeon® is the only fusion inhibitor
approved by the FDA for use in antiretroviral therapy. Recently the rate of new prescriptions for
Fuzeon® dropped by approximately 50 percent because of the apparent concern over patient
compliance given the burdensome multiple injections daily. There are multiple fusion inhibitors
currently in the pipeline many with unique mechanisms for preventing fusion by the HIV virus.
Beyond the currently FDA approved drugs there are many new candidates and new approaches at
various stages of development. They include immune-based therapies as well as vaccines.
Chiron’s (NASDAQ: CHIR) Proleukin® is the lead candidate in the area of immunology. AIDS
related immune-based therapies are expected to include the use of immune stimulants or immune
modulators such as cytokines, to help expand the HIV-specific immunity. Proleukin® (IL-2) has
shown to increase CD4 cell counts at various stages of HIV disease. Also, since latent virus remains
present in many cells and lymphoid tissues of the body, IL-2 may play an important role in
“flushing-out” these hidden pools of viruses. With multiple immune-based therapies currently in
development this new approach to attacking HIV may have a bright future. While most likely used
as adjunct therapy these immune-based therapies must show long term effects before they are
considered the next step to fighting HIV.
Many other novel approaches to attacking HIV are currently in development. These include
integrase inhibitors which prevent the virus from integrating itself into the genetic code of an
infected cell (Merck Pharmaceutical, NYSE: MRK); maturation inhibitors which prevent the virus
from maturing, rendering it unable to infect new cells (Panacos Pharmaceuticals); zinc finger
inhibitors which attack HIV’s inner core (Hubriphar); and devices such as Aethlon Medical’s
(OTC: AEMD) Hemopurifier™ which may offer exciting adjunct solutions to traditional anti-viral
therapy. These more novel approaches appear to have a lot of potential; however, currently
scientific data on these mechanisms is often minimal and require more data to determine their long
term safety and efficacy.
Finally, the worldwide demand and competition for an effective preventative HIV vaccine is intense.
Currently many health organizations as well as drug manufacturers are attempting to use
combinations of vaccine agents to limit the spread of HIV whether it be from person to person or
the prevention of further infection within a patient’s body. Many new vaccine strategies, preventive
and/or therapeutic, that result in production of both anti-HIV antibodies and cytotoxic T-cells
(CTLs), are now being pursued. ALVAC vCP1521 by Aventis Pasteur (NYSE: SNY) is a
promising vaccine that is delivered in a canarypox virus vector. AIDSVAX B/E by VaxGen Inc.
(OTC:VXGN.PK), which is a new formulation of a previously failed vaccine, uses a regulatory HIV
protein as its delivery mechanism. Both AIDSVAX B/E and ALVAC vCP1521 are currently in Phase III
studies. AIDSVAX may also serve as an effective booster to other vaccines currently in
development.
3
2.
THE HIV LIFE CYCLE
The human immunodeficiency virus (HIV) is a retrovirus and recognized as the etiologic agent of
acquired immunodeficiency syndrome (AIDS). That is, HIV infection causes a slowly progressive
deterioration of the immune system, which results in AIDS. HIV specifically infects cells that have
the CD4 receptor on their surface. Cells with the CD4 receptor are critical components of the
immune system and include T lymphocytes, monocytes, macrophages and dendritic cells. The
devastating effects of HIV are largely due to the multiplication of the virus in these cells and the
resulting dysfunction and destruction of the cells. The virus inserts its own RNA into a host cell’s
DNA, preventing natural cell processes and commencing production of HIV in the host organism.
The virus’ RNA is converted to DNA using the reverse transcriptase enzyme, and the DNA is
integrated into the host organism’s genome.
Viral infection occurs when the virus binds to a host cell, enters the cell and, by commandeering the
host cell’s own reproductive machinery, creates thousands of copies of itself within the host cell.
This process is called viral replication. Thus, viruses hide their own genome in the DNA of the cell,
and then, when the cell tries to make new proteins, it makes new viruses as well. This turns the
cell into a sort of HIV factory. In people infected with HIV, over 10 billion new copies of the virus
can be made every day. So it is easy for HIV to spread quickly through the body.
Scientists have demonstrated that the initial step of HIV infection involves the specific attachment
of the virus to the CD4 receptor on the surface of human immune system cells. A specific
glycoprotein, gp120, located on the surface of the virus, binds with high affinity to the CD4
receptor, as well as, to the CCR5 co-receptor which also enables fusion of HIV with the cell
membrane after binding of the virus to the CD4 receptor. This fusion step results in entry of the
viral genetic information into the cell and subsequent viral replication. It is interesting to note that
researchers have demonstrated that attachment alone is not sufficient to enable the virus to enter
the cell and initiate viral replication.
Although HIV infects a variety of cells, its main target is the T4-lymphocyte (also called the “Thelper cell”). These blood cells are important because they tell other infection-fighting cells when to
start working. The T4-cell has multiple CD4 receptors, or proteins, on its surface.
Thus, HIV destroys CD4 cells, and when the number of CD4 cells drops to a certain level because of
ongoing HIV infection, the body's immune system weakens. When these infections occur, or when
the number of CD4 cells drops below a certain level, a person with HIV infection is said to have
AIDS.
4
The HIV Life Cycle
1. Free Virus
HIV
Entry Inhibitors
2. Attachment: HIV’s gp120 binds to the cell at two
receptor sites: CD4 and CCR5.
gp120
CD4 &
CCR5
3. Fusion: The membranes of the virus and the
cells fuse and the contents are emptied into the
cells.
4. Reverse Transcription: Virus’ instructions
(viral RNA) are translated (transcription) into
cell instructions (viral DNA) by the reverse
transcriptase enzyme.
reverse transcriptase
HIV
RNA
Reverse
Transcriptase
Inhibitors
integrase
5. Integration: Newly made HIV DNA
moves to the cell’s nucleus to
“reprogram” the cell by combining with
the cell’s own DNA by the integrase
enzyme.
HIV DNA
6. Transcription and Translation: When
the “reprogrammed” cell divides, the viral
DNA is “read” and long chains of viral
proteins are made.
Integrase
Inhibitors
protease
7. Assembly: Viral protein chains, enzymes
and RNA are cut in smaller pieces by the
protease enzyme and come together to
form a new virus.
Protease
Inhibitors
8. Budding: New virus escapes the
cell taking some of the cell
membrane with it.
9. New virus: Once HIV-infected, the
cell can produce thousands of new
HIV particles that will search new
cells to infect and when they break
free, damage and cause the death
of the cells.
5
3.
MUTATIONS AND RESISTANCE
HIV is notorious for its ability to change, or mutate, and thereby evade the effects of drugs. HIV
infection is characterized by high rates of viral replication, eventually leading to depletion of CD4
cells and disease progression. A high frequency of replication results in a high frequency of viral
mutations, in turn this will result in many different strains of virus, each with slightly different
genes. Secondly, the mutation rate in HIV is very high because the enzyme responsible for copying
the viral genetic code is inefficient and makes numerous mistakes. It has been calculated that every
possible single point HIV mutation may occur more than 10,000 times a day in an infected person.
Through these mutations the HIV virus is able to develop resistance to antiretroviral drugs. The
development of drug resistance is the most common cause of treatment failure.
Mutations are random small differences that the HIV virus produces when copying itself in the
infected patient. When a mutation changes the portion of the virus with which the drugs are meant
to target and interfere with, it can keep the drugs from working. When a drug no longer works
against HIV, this is called drug resistance. The virus with the mutation is resistant to the drug. The
aim of antiretroviral therapy is to suppress viral replication for as long as possible, to
keep mutations to a minimum and so limit the appearance of resistant variants.
Resistance can develop to all drugs, including all classes of anti-HIV drugs, as well as, drugs taken
to treat opportunistic infections.
Resistance is least likely to develop if treatment is based on a combination of drugs. With this
approach, resistance takes longer to develop because a virus strain resistant to one drug could still
be sensitive to another. To overcome the action of two or more drugs simultaneously the virus has
to acquire multiple mutations. Its chances of getting multiple mutations in the right combination to
resist a number of drugs are much smaller than its chance of acquiring a single mutation that
enables it to resist just one drug. Therefore, properly sequencing HIV drug treatment allows for the
maximum number of options and alternatives to be available for the long term. Specific
combinations of multiple mutations are highly unlikely to exist before anti-HIV therapy is started.
Other causes of treatment failure include: outgrowth of resistant strains from residual replication at
"hidden sites" (such as the brain) not easily reached by anti-HIV drugs; gastrointestinal intolerance,
leading to low drug levels in the blood; simultaneous illness affecting drug availability to the body;
drug side-effects necessitating withdrawal of treatment; new infection by drug-resistant virus;
failure to keep to treatment schedule; and drug interactions reducing blood levels of anti-HIV drugs.
6
4.
NEW GOVERNMENT GUIDELINES
The latest government guidelines were issued October 29, 2004 and are available at
www.hivatis.org. As in previous guidelines, therapy is recommended for all patients who have
symptoms of HIV infection. The guidelines continue to reinforce the importance of adherence and of
maintaining a strong patient-physician relationship to ensure that the medications will continue to
be effective. The updated guidelines are more focused on when to initiate therapy as well as the
specific drug combinations that will be most effective in treating each individual patient. The
guidelines also focus on which drugs or drug combinations should be avoided and the means to
advance therapy once a resistance has formed. The guidelines suggest that “…asymptomatic
treatment-naïve patients with CD-4 T cell count > 350 cells/mm3; the viral load recommendation to
defer or to consider therapy has been increased from 55,000 to 100,000 copies/ml. This is based on
more recent data supporting HIV RNA level of >100,000 copies/ml being a stronger predictor of
disease progression than >55,000 copies/ml, though even at these CD-4 and viral load levels, the
risk of disease progression is still relatively low. Most experienced clinicians will defer therapy with
quarterly and laboratory evaluation.” 1 Treatment should also be considered when CD-4 cell counts
reach or fall below 350. Once a physician determines that antiretroviral treatment should be
initiated the panel has provided drug recommendations that physicians may follow when initiating
HAART in treatment-naïve patients. As in previously updated guidelines the panel preached 100
percent adherence as to help stem resistance development. The panel led by John Bartlett of John
Hopkins University and H. Clifford Lane of the National Institute of Health also focused on side
effects and their effect on patients’ compliance. The updated guidelines also focus on special
populations within the community of infected patients, including those co-infected with Hepatitis and
HIV, and the means by which to conduct their antiretroviral therapy.
The data to support 350 CD-4 T-cells as an appropriate cut-off are limited. Scientists focus more on
the patient’s HIV RNA viral load levels in deciding whether or not to initiate treatment. Scientists
are still trying to find the ideal time to begin antiretroviral treatment. In any event, it is clear that
there is a need to balance the benefits of therapy with the potential side effects and toxicities. Only
further study will clarify these issues.
1
AIDSinfo (Service of the U.S. Department of Health and Human Services). For further information please visit:
www.hivatis.org
7
5.
HIV/AIDS STATISTICS WORLDWIDE
Currently there are 39.4
million people in the
world living with HIV
Children under 15 years
2.2 million (2.0 - 2.6 million)
and AIDS.
Last year
alone 3.1 million people
People newly
Total
4.9 million (4.3 - 6.4 million)
died
of
AIDS
and
infected with HIV Adults
4.3 million (3.7 - 5.7 million)
in 2004
another
4.9
million
Children under 15 years
640 000 (570 000 - 750 000)
AIDS deaths in
people
were
newly
Total
3.1 million (2.8 - 3.5 million)
2004
Adults
2.6 million (2.3 - 2.9 million)
infected. These numbers
while still staggering
Children under 15 years
510 000 (460 000 - 600 000)
have
been
slightly
(source www.UNAIDS.org)
decreasing in the past
few years. Although the decrease in the number of HIV/AIDS incidences may seem quite promising
we are still far from ending this epidemic. The developed world is now reaching out to try and help
the regions most stricken with HIV and AIDS. Through more advanced, more powerful drugs and
through and ever expanding HIV awareness movement the world can hopefully turn the tide on this
deadly virus. The Sub-Saharan area of Africa is the world’s region hardest hit by HIV and AIDS with
a substantial portion of new infections coming from heterosexual sex. There are approximately 2528 million people in this region living with HIV/AIDS but hopefully through better education on safer
sex and other methods of HIV prevention this number will decrease in the near future. The CDC
fears that approximately 45 million people will become infected with HIV between 2003 and 2010.
It is predicted that some 40% of these infections will occur in Asia and Sub-Saharan Africa. Asia and
in particular, China, is an area of concern for the global prevention of HIV where there is currently a
growing epidemic. There are approximately one million people living with the disease in China and
some 8 million living with the disease in Asia and the Pacific islands. There is a common
misconception the AIDS epidemic is under control in the developed world or that the disease can be
easily managed through anti-HIV drug treatment. The current drug therapies are only able to
postpone the onset of AIDS and many of the drugs currently on the market are accompanied by
multiple, sometimes severe, side effects.
Number of people Total
living with
Adults
HIV/AIDS in 2004 Women
39.4 million (35.9 - 44.3 million)
37.2 million (33.8 - 41.7 million)
17.6 million (16.3 - 19.5 million)
ADULTS AND CHILDREN ESTIMATED TO BE LIVING
WITH HIV/AIDS, END 2004
(Source: UNAIDS: The Joint United Nation Programme on HIV/AIDS)
8
HIV/AIDS in the United States
The CDC estimates that in the United States there are approximately 850,000 to 950,000 people
living with HIV infection. Approximately one-quarter do not know they are infected. The CDC also
estimates that some 40,000 new infections are occurring each year. Approximately half of these
infections are in people under the age of 25. Of these new infections 70 percent are men and 30
percent are women. Of newly infected men 60 percent were infected through homosexual sex, 25
percent through intravenous (IV) drug use and 15 percent through heterosexual sex. Within the
group of newly infected men 50 percent are black, 30 percent are white, 20 percent are Hispanic
and very small percentages are members of other racial/ethnic groups. More than half of the new
infections occur in blacks.
There is a growing concern in the United States as well as throughout the world for the increased
number of women becoming infected. The CDC predicts that over time an increasing percentage of
newly infected persons will be female while newly infected male numbers will decline. From 1985 to
2002 the number of adult/adolescent women reported with AIDS cases in the United States rose
from 7 percent to 26 percent. Of new infections among women 75 percent were infected through
heterosexual sex and 25 percent through intravenous (IV) drug use. Of newly infected women 64
percent are black, 18 percent are white, 18 percent are Hispanic and small percentages are
members of other racial/ethnic groups.
Currently there are 405,926 persons in the United States living with AIDS. 524,000 people in the
United States have died from AIDS or AIDS related diseases. There is good news however; the
estimated annual number of AIDS-related deaths in the United States fell from 19,005 deaths in
1998 to 16,371 deaths in 2002. This is most likely due to increased strength and efficacy of newly
discovered drugs and treatments.2
New AIDS Cases, Reported in 2003
Less than 90
90 to 369
370 to 840
More than 840
Top Five States for new AIDS
Cases: 50.14%
(1)
(2)
(3)
(4)
(5)
New York- 14.87%
California- 13.13%
Florida- 10.38%
Texas- 7.52%
Georgia- 4.24%
(source: www.statehealthfacts.org)
2
UNAIDS, CDC, The American Foundation for AIDS Research (amfAR). CDC statistics for 2004 will be available in late
2005 and are available at: www.cdcnpin.org
9
6.
ANTIVIRAL DRUGS: NRTIS, NNRTIS, AND PIS
There are currently 25 (2 forms of saquinavir) approved antiviral drugs for HIV3. These drugs are
usually used in combinations of three or more to create an effective antiviral therapy and are
divided into four classes of agents which presently include: nucleoside reverse transcriptase
inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors
(PIs); and the newest class of antiviral drugs known as fusion inhibitors (please see section 7).
Currently Fuzeon® developed by Roche Pharmaceuticals is the only fusion inhibitor approved by the
FDA. Each class of drug has its own unique mechanism for attacking HIV.
Reverse Transcriptase Inhibitors
Reverse Transcriptase Inhibitor drugs stop HIV from multiplying by blocking the reverse
transcriptase enzyme. This enzyme changes HIV’s genetic material (RNA) into the form of DNA.
This step has to occur before HIV’s genetic code gets combined with an infected cell’s own genetic
material. There are two types of reverse transcriptase inhibitors: the “nucleoside” reverse
transcriptase inhibitors and the “non-nucleoside” reverse transcriptase inhibitors.
Nucleoside
analogues mimic the building blocks used by reverse transcriptase to make copies of the HIV
genetic material.
These fake building blocks disrupt the copying. Non-nucleoside reverse
transcriptase inhibitors (NNRTIs) physically prevent the reverse transcriptase from working.
REVERSE TRANSCRIPTASE
Reverse Transcriptase Inhibitor drugs stop HIV from
multiplying by blocking the reverse transcriptase enzyme.
HIV RNA
HIV DNA
Protease Inhibitors
Protease Inhibitors are designed to inhibit the function of the HIV protease enzyme. Protease acts
at a different stage of the replication process than reverse transcriptase (RT). Protease inhibitors act
by preventing cleavage of HIV viral polyproteins into active proteins by blocking the enzyme’s active
site. Cleavage of HIV viral polyproteins into active proteins occurs during the process by which HIV
normally replicates. The goal of the protease inhibitor thus is to stop the protease from helping to
assemble a new virus by preventing (sometimes referred to as gumming up) protease from cutting
long chains of proteins into shorter pieces that HIV needs to assemble a new virus. They interrupt
the way HIV uses a healthy cell to make more viruses.
PROTEASE
PROTEASE
PROTEASE
INHIBITOR
HIV PROTEIN
SHORTER CHAIN
OF HIV PROTEIN
Individual
proteins that
make new
HIV particles
Individual
enzymes that
help build new
HIV particles
Protease
Inhibitors
resemble pieces of the
protein
chain
that
protease normally cuts. By
“gumming
up”
the
protease “scissors”, HIV
protease inhibitors prevent
protease from cutting long
chains of proteins and
enzymes into the shorter
pieces that HIV needs to
make new copies of itself.
3
Information was derived from AIDS.org. The mission of AIDS.ORG is to help prevent HIV infections and to improve the
lives of those affected by HIV and AIDS by providing education and facilitating the free and open exchange of knowledge
at an easy-to-find centralized website. For more information please visit: www.aids.org
10
Fusion Inhibitors
Fusion inhibitors prevent infection by attacking the virus outside of the cell. They inhibit the virus’s
ability to fuse to the healthy cells before it can enter and begin the replication process. It targets
the cycle when HIV attaches itself to the T-cell (site gp41 molecule on the virus). Fusion inhibitors
are able to block viral fusion by interfering with certain structural arrangements with gp41 that is
required for HIV to fuse and enter a host cell.
FUSION
INHIBITOR
gp41
Fusion inhibitors prevent HIV from
fusing with healthy cells thus
preventing HIV infection. Fusion
inhibitors work by either attacking
the HIV virus’s ability to fuse to the
healthy cell or by protecting the cells
receptors.
gp41
6.1 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS / NUCLEOSIDE
ANALOGUES / “NUKES”
Nucleoside analogue reverse transcriptase inhibitors (NRTIs) are the main class of reverse
transcriptase inhibitors. NRTIs are converted into their active form (known as the triphosphate
form) within cells by a process known as phosphorylation. They then resemble the nucleosides
found in the human cell.
NRTIs attempt to disrupt the construction piece of proviral DNA during reverse transcription.
Instead of taking up a nucleoside from the supply in the cell, reverse transcriptase uses the
nucleoside analogue drug instead as a faulty building block. These “faulty” building blocks do not
form the necessary chemical bonds with the natural nucleosides and therefore the DNA chain is
unable to hold together. The incomplete chain is unable to correct itself and the process of viral
replication is interrupted.
Reverse Transcriptase
Nucleoside Analogues or “Nukes” incorporate
themselves into the structure of the viral DNA,
rendering the DNA useless and preventing it
from instructing the infected cell to make
additional HIV viruses.
HIV RNA
Nucleoside Analogues
HIV DNA
The major drawback of these drugs is that they may be taken up when healthy cells start to
reproduce thus preventing production of healthy new cells. According to researchers reverse
transcriptase have a much higher affinity for nucleosides than DNA polymerase, the human enzyme
equivalent to the nucleoside analogues. The likelihood of nucleoside analogues halting reproduction
11
in health cells is not very good. Human cells are also able to fix problems in their DNA production
during cell reproduction.
NRTIs are mainly for use in combination therapies. When two NRTIs are used in combination with
other anti-HIV drugs (usually an NNRTI or PI)-usually a total of 3 drugs- then the combination may
be able block the replication of HIV. This combination is known as a drug cocktail. There are several
drugs in the NRTI class that are currently used as part of antiretroviral combination therapy. NRTIs
are expected to remain the most robust HIV class in terms of overall sales.
GlaxoSmithKline (NYSE: GSK) continues to have the strongest franchise in NRTIs and currently
holds just over 50 percent of the market share in NRTIs. GlaxoSmithKline’s leading NRTI is
Combivir®, which is a combination of Retrovir® and Epivir®, sold as a single drug to be used in
combination with other antiretroviral drugs. The appeal of Combivir® is its easy dosing regimen
which is a single-pill twice-daily. GlaxoSmithKline’s strong early start in the anti-HIV drug market
was also due in part to Trizivir® (Retrovir®, Epivir®, and Ziagen®) which combines all three of
GlaxoSmithKline’s NRTIs and may also be taken with other antiretroviral drugs. Recent studies have
shown that Trizivir®, when taken alone, does not have the same efficacy as a drug cocktail
containing a PI or NNRTI. This may dent the drug giant’s hold on the HIV market. GlaxoSmithKline
achieved sales of $2.73 billion (+4%) in the NRTI market in the twelve months ended in September
2004. NRTI sales dominate GlaxoSmithKline’s anti-HIV sales. Sales by product for fiscal year 2004
were as follows: Combivir® – $1,067 M (+4%); Trizivir® – $602 M (-8%); Epivir® – $549 M
(+7%), Ziagen® – $290 M; Retrovir® – $80 M (+2%).
Currently GlaxoSmithKline holds 45 percent share of the total weekly prescription in the anti-HIV
market. GlaxoSmithKline is being contended with by up and coming companies in the anti-HIV
market such as Gilead Sciences. GlaxoSmithKline is hoping that their new drug Epzicom®, a oncedaily combination of Ziagen® (abacavir) and Epivir® (3TC), will reaffirm their hold on the NRTI
market.
Gilead Sciences (NYSE: GILD) now holds the number two spot in NRTI sales passing BristolMeyers Squibb. This is due in large part to the 903 study which showed Gilead’s Viread® to have
equivalent efficacy as Bristol-Meyers Squibb’s Zerit® but with a better safety profile. In particular,
Zerit® caused a much greater increase in the lipid profile which consists of triglyceride and
cholesterol levels. Viread® caused an average increase of 4 mg/dL in triglycerides compared to an
increase of 104 mg/dL in Zerit®. Zerit® also caused cholesterol levels to go 22 mg/dL higher than
Viread®. Viread® has also been proven to work quite well as a salvage drug, lowering viral loads
in patients that had developed mutations to all three classes of antiretroviral drugs. Viread® holds
nearly 20 percent of NRTI prescriptions and Gilead reports that approximately 150,000 patients are
on Viread® worldwide and 25-30 percent of all HIV patients use Viread® in their therapy.
Gilead’s Emtriva® (FTC) is very similar to GlaxoSmithKline’s Epivir® (3TC) and will help Gilead
challenge GlaxoSmithKline’s combination drug Combivir®.
Emtriva® can be combined with
Viread®, a combination with more efficacy than the combination of AZT and 3TC (Combivir®). The
combination of Viread® (tenofovir) and Emtriva® (FTC) is known as Truvada® and was approved
by the FDA in August of 2004. Truvada®, a once-daily tablet should significantly penetrate
GlaxoSmithKline’s sales in combination drug therapy. Gilead’s total HIV sales were $908.4 (+58%)
million for the fiscal year 2004. Sales by product for the fiscal year 2004 are as follows: Viread® $782.9 M (+38%); Emtriva® - $57.6 M.
In 2005 the first patent expiry in the HIV market will occur, with the expiry of GlaxoSmithKline’s
Retrovir®. The patents of Bristol-Meyers Squibb’s Videx® and Roche’s Hived® will expire in 2006.
The high price point and strong market in HIV will make this an attractive market for generic
competition.
APPROVED NRTIS
Retrovir® (AZT, zidovudine) – GlaxoSmithKline (NYSE: GSK)
Commonly known as AZT, Retrovir® was the first FDA-approved HIV antiviral (March 1987). AZT is
the most studied drug on the market because it has been around so long. Since it has been studied
more often than any other drug, Retrovir® is prescribed more often than any other drug.
Retrovir® is given to women quite often to prevent transmission from mother to baby.
12
The side effects of AZT are similar to those of many anti-HIV drugs. The more severe side effects
include anemia (shortage of red blood cells), myopathy (muscle pain and weakness), and
neutropenia (low number of specific white blood cell).
The benefit of AZT monotherapy appears to be minimal and Retrovir® is most often taken with
other antiretroviral drugs. It is taken as one 300-mg tablet twice a day and is also available in
Combivir® and Trizivir®. There are multiple generic versions of Retrovir currently being
manufactured but none have been pre-qualified by the World Health Organization. AZT is effective
against HIV in the brain and central nervous system. AZT is the only anti-HIV drug approved for use
during pregnancy. Retrovir® achieved sales of $80 million in 2004 (+4%).4
Epivir® (3TC, lamivudine) – GlaxoSmithKline (NYSE: GSK)
Epivir® was approved by the FDA in November of 1995. 3TC is able to reduce HIV resistance to
AZT. When AZT and 3TC are taken in combination they work synergistically.
The recommended dosage of Epivir® is either one 300-mg tablet a day or one 150-mg tablet twice
a day. Recent studies have shown similar efficacy if the same total dosage is taken once a day. It
can be taken with or without food. 3TC is available in Combivir®, Trizivir®, and Epzicom®.
Lamivir, a generic version of 3TC, was recently placed back on the World Health Organization’s
prequalified list and is being manufactured by the Indian company Cipla. There are other generic
version in the works however they have not been placed on WHO’s pre-qualified list. 3TC in
combination with other drugs has been shown to be safe and effective against primary HIV infection
The side effects of Epivir® include nausea, vomiting, headaches, and rare cases of hair loss.
Epivir® achieved sales of $549 million in 2004 (+4%).5
Combivir® (AZT + 3TC) – GlaxoSmithKline (NYSE: GSK)
Approved in September 1997, Combivir® contains AZT and 3TC, a combination that works
synergistically. The addition of 3TC in combination with AZT appears to delay the development of
resistance significantly, and improves anti-HIV activity.
In a pill taken twice a day, Combivir® provides an alternative regimen to 150 mg 3TC twice a day
plus AZT 600 mg per day in divided doses. This drug form reduces pill intake for these two drugs to
two per day instead of up to eight and can be taken with food, or between meals. This convenience
has been a real advantage for Combivir®, meaning fewer missed doses and better patient
compliance making it highly attractive to HIV specialists.
Combivir®’s side effects are those associated with most antiviral drugs including nausea and
vomiting as well as those side effects associated with AZT and 3TC. There is a generic version of
Combivir known as Duovir manufactured by Cipla that was recently restored to the World Health
Organization’s prequalification list. Combivir® achieved sales of $1,067 million in 2004 (+4%).6
Ziagen® (abacavir) – GlaxoSmithKline (NYSE: GSK)
During treatment abacavir penetrates the spinal fluid and thus affects the central nervous system.
This may help it prevent mental problems such as dementia. Abacavir still appears to work when
the virus has developed resistance to other antiretroviral drugs. Ziagen® is intended to work with
other anti-HIV drugs.
4
Information for the drugs listed in this and the following sections was derived from AIDS.com, AIDSmap.com,
aidsinfonyc.com, and the respective company websites. AIDS.COM is published by the American International AIDS
Foundation which is a Non-Profit Charitable Organization committed to providing timely, accurate and easy to understand
information about AIDS and HIV to a global audience. AIDSmap.com is a website that includes completely searchable
databases of HIV treatment and care, worldwide HIV organization listings, and one of the most comprehensive ranges of
patient information available on the web. Aidsinfonyc.org is a linked collection of information pages for people living with
HIV and AIDS from community based organizations in New York City. (please see www.aids.com, www.aidsmap.com,
www.aidsinfo.org, and www.gsk.com for more information)
5
Ibid
6
Ibid
13
The side effects of Ziagen® include those associated with most anti-HIV drugs. In addition to these
side effects about 8 percent of patients who take abacavir have an allergic reaction. Patients’
symptoms include fever rash, headache, cough, shortness of breath and sore throat. In rare cases,
people had serious reactions after restarting abacavir. There are two generic versions of abacavir
currently available Virol by Ranbaxy and Abavir by Genixpharma.
The normal adult dosage is a 300-mg capsule taken twice a day. Ziagen® can be taken with or
without food. Ziagen® achieved sales of $290 million in 2004 (0%).7
Trizivir® (abacavir + AZT + 3TC) – GlaxoSmithKline (NYSE: GSK)
Trizivir® was approved by the FDA in November of 2000. Trizivir® is a combination of three NRTIs.
Each Trizivir® capsule contains 150 mg of Epivir® (3TC), 300 mg of Ziagen® (abacavir) and 300
mg of Retrovir® (AZT). One tablet is taken twice-daily with or without food. Trizivir® is considered
less effective than a combination that includes either a PI or an NNRTI. It is rarely taken alone.
The side effects of Trizivir® include those associated with all three components. Trizivir achieved
sales of $602 million in 2004 (-8%).8
Zerit® (stavudine, d4T) – Bristol-Myers Squibb (NYSE: BMY)
Approved in June 1994 and commonly called d4T, Zerit® is usually taken as one 40-mg capsule
twice a day. Zerit® can be taken with or without food.
Common side effects are headaches, hypertension, and fatigue. Peripheral neuropathy is also a
potentially severe side effect of d4T and, in some cases, lowering the dosage can eliminate the
peripheral neuropathy and still provide good viral suppression. Lypodystrophy and in particular loss
of subcutaneous fat from the face, arms, legs, is another side effect of d4T. Lactic acidosis or
buildup of lactic acid in the blood may also occur.
There are several generic version of d4T including Stavir by Cipla, Virostav/Avostav by Ranbaxy,
Stag by Genixpharma, Stavex by Aurobindo, and Stavir by GPO. The World Health Organization
recommends that HIV treatment begin with a combination of drugs including d4T. Zerit® achieved
sales of $272 million in 2004 (-23%).9
Videx® (didanosine, DDI) – Bristol-Myers Squibb (NYSE: BMY)
Videx® was approved in October 1991 and is commonly called DDI. Videx®’s dosage depends on
the patient’s body weight. Videx® comes in chewable tablets or as a powder that can be dissolved
in water. Videx® can be taken once a day in two 200 mg tablets; however, the FDA prefers twice
daily dosing. To maximize absorption, it should be taken at least one hour before or two hours after
a meal.
Side effects of Videx® include those common to most anti-HIV drugs including diarrhea, headaches,
vomiting and rash. Videx®’s more serious side effects are peripheral neuropathy, pancreatitis, and
lactic acidosis. The enteric coated version of Videx®, Videx® EC improves GI tolerability and
reduces pill burden to one capsule daily.
Generic versions of ddl are Dinex EC by Cipla, Viro-Z and Aviro-Z by Ranbaxy, and Divir
manufactured by the Thai government. Videx® achieved sales of $274 million in 2004 (+3%).10
Hivid® (zalcitabine, ddC) – Roche Pharmaceuticals (OTC: RHHBY.PK)
7
Ibid
Ibid
Information from the Bristol-Meyers Squibb Company website. For further detail please visit: www.bms.com
10
Ibid
8
9
14
Hivid® was approved in June 1992 and is commonly called ddC. Hivid® is usually taken as one
0.75-mg tablet three times a day. It also comes in liquid form. Hivid® is able to penetrate the blood
brain barrier.
Due to Hivid®’s inconvenience in dosing and serious side effects it is very rarely used to treat HIV
anymore. Common side effects of Hivid® include those common to other antiretroviral drugs as well
those specific to ddC including rashes, chest pain, fever, nausea, changes in liver function and
mouth sores. The more serious side effects of ddC include peripheral neuropathy and in rare cases
pancreatitis.
Hivid®’s patent expires in 2006.11
Viread® (tenofovir) - Gilead Sciences (NasdaqNM: GILD)
Viread® was approved by the FDA in October of 2001. Tenofovir, the active ingredient in Viread®,
appears to have very little cross resistance with other antiviral drugs. This makes Viread® one of
the most important drugs in salvage therapy. Cross resistance refers to the ability of a virus to
become resistant to multiple antiviral drugs after becoming resistant to a single antiviral drug.
Viread® is able to work against several strains of HIV that are already resistant to AZT, ddC, or ddl.
Tenofovir is technically a NtRTI or nucleotide analogue reverse transcriptase inhibitor. NtRTIs are
essentially the same as NRTIs except that they are in their native form so they do not require the
machinery in certain cells to activate the drug (known as phosphorylation) allowing them to work in
a wide variety of infected cells.
The normal adult dose of tenofovir is a 300 mg pill taken once a day with or without food.
Viread®’s side effects include those common to most anti-HIV drugs including nausea, vomiting and
loss of appetite. Tenofovir may also cause damage to the liver and kidneys because of the
increased levels of the enzymes creatine and transaminases.
Gilead hopes to use tenofovir as an effective tool in the prevention of HIV infection as well.
Tenofovir is also available in Truvada®, a combination of Viread® and Emtriva® (emtricitabine).
Viread® achieved sales of $782.9 million in 2004 (+38%).12
Emtriva® (emtricitabine, FTC) – Gilead Sciences (NasdaqNM: GILD)
Emtriva®’s active ingredient is emtricitabine also known as FTC. The FDA approved Emtriva® in
July of 2003. Emtricitabine is similar to 3TC and is susceptible to “cross resistance” especially for
those who have taken Epivir® (3TC). If the virus has developed a resistance to either drug it will
probably be resistant to the other.
Emtriva® is taken once a day in 200 mg tablets. Emtricitabine is available in the combination drug
Truvada® along with tenofovir.
Emtricitabine suffers from the common side effects of many anti-HIV drugs such as headache,
diarrhea, nausea, and rash. Emtricitabine seems to have few if any negative interactions with other
anti-HIV drugs. There is some evidence that emtricitabine has fewer side effects than 3TC.
Emtriva® achieved sales of $57.6 million in 2004.13
Truvada® (emtricitabine + tenofovir) – Gilead Sciences (NasdaqNM: GILD)
Truvada® was approved by the FDA in August of 2004 and is a combination pill that contains two
drugs tenofovir (Viread®) and emtricitabine (Emtriva®).
11
12
13
Information from the Roche company website. Please visit www.roche.com for further detail.
Information from the Gilead Sciences company website. Please visit www.gilead.com for further detail.
Ibid
15
Truvada® is taken as single dosage of 300 milligrams of tenofovir and 200 milligrams of
emtricitabine combined into one tablet. It is taken once-daily orally.
Truvada®’s side effects include those common to many anti-HIV drugs and more specifically to
those side effects associated with tenofovir (Viread®) and emtricitabine (Emtriva®).
A major benefit of any combination drug is the convenience that it provides to the patient, this will
translate into fewer missed doses. Thus many doctors favor prescribing combination drugs to their
patients.14
Epzicom® (abacavir + 3TC) – GlaxoSmithKline (NYSE: GSK)
Epzicom® combines abacavir (Ziagen®) and 3TC (Epivir®) and was approved by the FDA in August
2004. It is known as Kivexa® in Europe.
Epzicom® is a single dosage tablet combination that consists of 600 milligrams of abacavir
(Ziagen®) and 300 milligrams of 3TC (Epivir®). It is taken once daily.
The side effects of Epzicom® are those similar to abacavir and 3TC which include nausea, vomiting,
fatigue, and headaches.
One major drawback of Epzicom® is what is referred to as a hypersensitivity reaction. This usually
occurs in about 8% of people taking abacavir. If this occurs the patient must stop taking abacavir
and cannot take it again because of a potentially fatal reaction.15
NRTIS IN DEVELOPMENT
Alovudine (MIV-310) – Medivir (Stockholm: MVIRb.ST)
Laboratory data shows promise for alovudine against HIV that has formed a resistance to other
nucleoside analogs. Alovudine is in Phase II trials. Data suggests alovudine probably cannot be
combined with AZT or d4T. Side effects are related to bone marrow damage which includes liver
toxicity and anemia. The compound is very similar to AZT however it has shown to be effective
against strains that are resistant to AZT. It may be available for once daily dosing.16
Elvucitabine (ACH-126) - Achillion Pharmaceuticals
Elvucitabine shows promise against HIV that has become resistant to several other nucleoside
analogues. Elvucitabine is taken once daily. Elvucitabine has also shown to be effective against
hepatitis B. Studies performed in 2003, of 50 mg and 100 mg doses showed bone marrow
suppression in patients, the studies were halted and lower doses will be studied. It appears that
elvucitabine will be taken as one pill, once a day. It is currently in late Phase II studies.17
MIV-210 (FLG) – Medivir (Stockholm: MVIRb.ST)
Currently in Phase I trials, MIV-210 shows promise against HIV that has become resistant to several
other nucleoside analogues. MIV-210 is a pro-drug of FLG. Pro-drugs are not directly active in
infected cells; they require an extra reaction within the body to become active within a cell. Because
MIV-210 is a fluoride nucleoside analog a watchful eye will be kept on hepatotoxicity, the main
reason for the failure of earlier fluoride nucleosides.18
14
Ibid
GlaxoSmithKline company website: www.gsk.com
Medivir company website and aindsinfoNYC.com (a linked collection of information pages for people living with HIV and
AIDS from community based organizations in New York City). For more information pleased see: www.medivir.se and
www.aidsinfonyc.org
17
Achillion company website. For more information please visit: www.achillion.com
18
Medivir company website
15
16
16
Racivir® (RCV) - Pharmasset Inc
Racivir® is very similar to FTC (Emtriva®). In laboratory studies Racivir® has shown to be active
against HIV and hepatitis B. Racivir®, during a Phase I/II study, was still showing anti HIV activity
as long as 2 weeks after the patient had stopped taking the drug. Pharmasset hopes that Racivir®
will be a single dosage taken once daily.19
Reverset™ (D-D4FC ) - Pharmasset, Inc/Incyte Corporation (NasdaqNM: INCY)
Reverset™ is a new drug that has shown promise with activity against HIV with resistance to the
drugs 3TC and AZT. Reverset™ is currently in Phase II studies and any side effects it may have
appear to be minor. Reverset™ is very close in structure to Racivir®. Reverset™ will most likely be
a once daily dosing and mainly used for salvage therapy. Reverset™ is currently entering Phase IIb
studies.20
SPD 754- Avexa Ltd. (ASX: AVX.AX)
SPD 754 is currently in Phase I studies and is showing good activity against HIV that is resistant to
the drugs 3TC and AZT. SPD 754 is showing strong activity against HIV. It will likely be available in
a once daily regimen. SPD 754 is also able to penetrate the cerebrospinal fluid (CSF), potentially
flushing out hidden pools of the HIV virus. It has an estimated target launch of 2009.21
19
20
21
Pharmasset company website. For more information please visit: www.pharmasset.com
Ibid
Avexa company website. For more information please visit: www.avexa.com.au
17
Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Brand
Name
Generic
Chemical
Name
Current
Phase
FDA
Approval
Manufacturer
Sales in
Millions
2004
%
Change
in
Sales
Retrovir®
Epivir®
Combivir®
zidovudine
lamivudine
zidovudine &
lamivudine
AZT
3TC
Approved
Approved
Approved
Mar-87
Nov-95
Sep-97
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
$80 M
$549 M
$1,067 M
4%
4%
4%
Ziagen®
Trizivir®
abacavir
abacavir &
zidovudine &
lamivudine
1592U89
Approved
Approved
Dec-98
Nov-00
GlaxoSmithKline
GlaxoSmithKline
$290 M
$602 M
0%
-8%
Zerit®
Videx®
Hivid®
Viread®
Emtriva®
Truvada®
stavudine
didanosine
zalcitabine
tenofovir
emtricitabine
emtricitabine &
tenofovir
d4T
ddl
ddT
PMPA
FTC
Approved
Approved
Approved
Approved
Approved
Approved
Jun-94
Oct-91
Jun-92
Oct-01
Jul-03
Aug-04
Bristol-Myers Squibb
Bristol-Myers Squibb
Roche
Gilead
Gilead
Gilead
$272 M
$274 M
N/A
$782.9 M
$57.6 M
N/A
-23%
3%
N/A
38%
N/A
N/A
Epzicom®
abacavir &
lamivudine
Approved
Aug-04
GlaxoSmithKline
N/A
N/A
Alovudine
Elvucitabine
MIV-210
Racivir®
MIV-310
ACH-126
FLG
RCV
Phase II
Phase II
Phase I
Phase I/II
Medivir
Achillion
Medivir
Pharmasset Inc
Reverset™
D-D4FC
Phase II
Incyte & Pharmasset
SPD754
Phase II
Avexa Ltd.
18
6.2 NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIS)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are the second class of anti-HIV drugs,
including delavirdine, loviride, and nevirapine, which act to combine directly with and block the
action of HIV’s reverse transcriptase enzyme. In contrast, nucleoside analogs block reverse
transcriptase by capping the unfinished DNA chain that the enzyme is constructing. By inhibiting the
enzymatic activity necessary for reverse transcription, NNRTIs successfully interfere with one of the
steps of the HIV life cycle and prevent the virus from being able to reproduce. It is the same point
in the life cycle interfered with by NRTIs. Unlike the NRTIs, however, the NNRTIs are not
incorporated into the viral DNA molecule, and therefore these compounds require no
phosphorylation by cellular enzymes in order to be active.
Reverse Transcriptase
NNRTIs bind directly to reverse transcriptase,
preventing the enzyme from converting RNA to DNA
NNRTI
HIV RNA
HIV DNA
Bristol-Myers Squibb’s (NYSE: BMY) Sustiva® continues to be the market leader in NNRTIs with
year 2004 revenue of $621 million an increase of 14 percent from 2003. Sustiva® currently has a
13.8% share of the new prescriptions in the NNRTIs and NRTIs combined. Sustiva® also continues
to be the most prescribed product among PIs and NNRTIs. Sustiva® has 65 percent of the new and
total NNRTI prescriptions. Sustiva®’s success is most likely to due to its low pill burden and oncedaily dosing. Either NNRTIs or PIs are the third part of the triple drug cocktail so they must
compete against each other for a share of the market. The major issue with NNRTIs is their
susceptibility to resistance and more importantly cross resistance. Because of NNRTIs susceptibility
to cross-resistance each patient will only be able to receive one NNRTI at one line of therapy.
Therefore choosing an NNRTI is very important for each individual patient. There are only three
approved NNRTIs including Viramune® by Boehringer Ingelheim, Sustiva® by Bristol-Myers
Squibb (NYSE: BMY), and Rescriptor® by Pfizer (NYSE: PFE). In the arena of NNRTIs there is
plenty of room for new drugs to enter and control a sizeable market share. In the next few years it
is safe to assume that Sustiva® will maintain its control over the NNRTI market. Without more late
stage efficacy data on new, promising NNRTIs such as TMC-125 and Capravirine, the market will
likely continue at its present state.
APPROVED NNRTIS
Viramune® (nevirapine) – Boehringer Ingelheim
Commonly known as nevirapine, Viramune® was the first FDA approved NNRTI, receiving approval
in June of 1996. Viramune® is taken as a 200 mg pill once a day for the first two weeks and twice a
day after that. This dosing schedule is to avoid serious side effects. Nevirapine has been shown to
be as effective as most PIs when used in triple drug cocktails. It is also able to penetrate the brain
and spinal fluids.
The most common side effect of nevirapine is a skin rash which develops in about 20-25 percent of
patients on Viramune®. This side effect is more common in women than men. Other side effects
include those common to anti-HIV drugs including fever, fatigue, headache and possible liver
damage. In some cases the liver damage can be fatal. Nevirapine can also be used to prevent
transmission of HIV from a pregnant woman to her child.
19
Two generic versions of nevirapine are manufactured, one by Cipla called Nevimune and another by
Aurobindo Pharma called Nevirex. Viramune® achieved sales of $409.2 million in fiscal year 2003 (8%).22
Sustiva® (efavirenz) – Bristol-Myers Squibb (NYSE: BMY)
Sustiva® was approved in September 1998 as the first once-daily anti-HIV drug for use in
combination regimens. Efavirenz is able to penetrate the central nervous system and in particular
spinal fluid which may help it prevent mental problems such as dementia. Sustiva® is usually taken
as three 200 mg pills once a day. It can also be taken as a 600 mg tablet that was approved for use
in 2002. Efavirenz is better suited to be taken with meals and it is recommended to avoid eating
high fat foods within a few hours of dosing because they will increase the amount efavirenz in the
blood.
The most common adverse side effects are nervous system symptoms (eg. Dizziness, trouble
sleeping, impaired concentration, drowsiness, and/or abnormal dreams) and mild to moderate rash.
These symptoms occur early and generally resolve within two to four weeks. Serious psychiatric
symptoms may occur but have been infrequently reported in patients receiving Sustiva®.
Generic versions of efavirenz include Efavir (Cipla), Estiva (Genixpharma), Viranz (Aurobindo),
Efferven (Ranbaxy). Efavirenz is as effective if not more effective as PIs when used in triple drug
cocktails. Sustiva® achieved sales of $621 million in fiscal year 2004 (+14%).23
Rescriptor® (delavirdine) – Pfizer (Agouron Unit) (NYSE: PFE)
Rescriptor® was approved in April 1997; however, it faces major problems because of the high
number of pills and multiple doses that must be taken each day. The recommended dose for adults
is 400 mg three times a day and it is available in pills of 100mg and 200 mg. This would force the
patient to take six 200 mg pills or twelve 100 mg pills per day. The 100 mg pills can be dissolved in
water to make them easier to swallow. Rescriptor® has no food restrictions.
Since resistance to one NNRTI almost always means resistance to all the drugs in this class, most
patients prefer Sustiva® because it is more potent.
Rescriptor® is typically well tolerated; it has similar side effects as other anti-HIV drugs including
headaches, fever, or a general sense of feeling ill. A rash occurring is the major side effect, similarl
to other NNRTIs. Rescriptor® may increase the level of some PIs in the blood stream and is being
considered in therapy along with PIs.24
NNRTIS IN DEVELOPMENT
Calanolide A – Advanced Life Sciences
Calanolide A is derived from a rain forest plant. Currently in Phase I/II human trials, calanolide A is
able to easily cross the blood-brain barrier and appears to survive in the bloodstream for an
extended period of time. Its side effects are mild and include dizziness, nausea, headache and an
oily taste in some patient’s mouths. Calanolide A is very potent against resistant strains of the HIV
virus, and is likely to be given as a twice-daily dosing. Currently development is on hold and
Advanced Life Sciences is developing other NNRTIs that are in the preclinical stage.25
Capravirine (AG1549) - Pfizer (Agouron Unit) (NYSE: PFE)
Capravirine is very effective against the wild type virus. In many cases it appears to be
approximately ten times stronger than the drugs nevirapine (Viramune®) and delavirdine
(Rescriptor®). Capravirine is effective because of its ability to prevent drug resistance. HIV
develops resistance in current NNRTIs in just one mutation while it takes 2 or 3 mutations to resist
22
23
24
25
Boehring-Ingelheim company website. For more information please visit: www.boehringer-ingelheim.com
Bristol-Meyers Squibb company website
Pfizer company website. For more information please visit: www.pfizer.com
Advanced Life Sciences company website. For more information please visit: www.advancedlifesciences.com
20
capravirine. The current dosage appears to be two 700 milligram tablets taken twice every day.
Capravirine is back in development and heading into Phase III trials after a brief development hold
because of vasculitis in dogs. Undetectable viral loads have been seen in patients through 49
months of treatment. Side effects appear to be those associated with most other NNRTIs.
Capravirine showed similar efficacy to triple drug “cocktails”.26
GW695634 – GlaxoSmithKline (NYSE: GSK)
GW695634, in Phase II trials, is a pro-drug of GW8248, a drug formerly produced by
GlaxoSmithKline. GW8248 is a compound that was found to be highly active against HIV.
GW695634 is broken down in the body and is able to produce GW8248 with more availability than if
the GW8248 had been taken in its original form. GlaxoSmithKline hopes GW695634 will be active
against strains of HIV that are resistant to other NNRTIs.27
TMC125 (etravirine) – Johnson & Johnson (Tibotec Unit) (NYSE: JNJ)
TMC125 has shown the ability to prevent HIV resistance longer than the first NNRTI drugs and is
active against some HIV strains that are resistant to NNRTIs. In one study TMC125 was reported to
be as potent as a five drug combination including drugs from each class. TMC125 is currently being
studied in Phase II trials. Once the proper dosage is determined TMC125 will move on to Phase III
testing.28
TMC278 (rilpivirine) – Johnson & Johnson (Tibotec Unit) (NYSE: JNJ)
TMC278, in Phase I/II human testing, has shown very promising early efficacy data, yet it is too
early in testing for any certainty on its long term effects. TMC278 was 10 to 20 times more active
than efavirenz (Sustiva®) in laboratory tests. Efavirenz showed resistance breakthrough after six
days while TMC278 showed none even after 30 days. TMC278 is also known as a DAPY
(diarylpyrimidine).29
KP-1461 – Koronis Pharmaceuticals
KP-1461 is a prodrug of KP-1212. KP-1461 requires a reaction within the body to become KP-1212
which is able to fight the HIV virus. It is currently in Phase Ia studies. KP-1212 does not appear to
have cross-resistance with currently approved antiviral drugs.30
DOT (dioxolane thymidine) – University of Georgia
DOT has been shown to be very active against all the nucleoside-resistant HIV-1 viral mutations. It
is currently in Phase I studies. While still very early in clinical trials, DOT has shown great promise
for patients who have developed resistance to contemporary antiretroviral regimens.31
26
Pfizer company website: www.pfizer.com
GlaxoSmithKline company website: www.gsk.com
28
Johnson & Johnson company website. For more information please visit: www.jnj.com
29
Ibid
30
Koronis Pharmaceuticals company website. For more information please visit: www.koronispharma.com
31
The 12th Conference on Retroviruses and Opportunistic Infections, February 22-25, 2005, a scientifically focused
meeting of the world's leading researchers working to understand, prevent, and treat HIV/AIDS and its complications.
Details from the conference are available at: www.retroconference.org
27
21
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Brand
Name
Generic
Chemical
Name
Current
Phase
FDA
approval
Manufacturer
Sales in
Millions
2004
%
Change
in Sales
Viramune®
nevirapine
BI-RG-587
Approved
Jun-96
Boehringer Ingelheim
$ 409.19 M*
-8%
Sustiva®
efavirenz
DMP-266
Approved
Sep-98
Bristol-Myers Squibb
$ 621 M
14%
Rescriptor®
delvirdine
U-901525/T
Approved
Apr-97
Pfizer (Agouron)
N/A
N/A
Calanolide A
Phase II
Capravirine
AG1549
Phase III
Advanced Life
Sciences
Pfizer (Agouron)
GW695634
Phase II
GlaxoSmithKline
etravirine
TMC125
Phase II/III
Johnson & Johnson
(Tibotec)
rilpivirine
TMC278
Phase I/II
Johnson & Johnson
(Tibotec)
KP-1461
Phase Ia
Koronis
Pharmaceuticals
DOT
(dioxolane
thymidine)
Phase I
University of Georgia
*2003 sales
22
6.3 PROTEASE INHIBITORS (PIS)
Protease Inhibitors (PIs) are able to inhibit the function of the HIV protease enzyme. Protease acts
at a different stage of the replication process than reverse transcriptase (RT), and so taking a PI in
combo with an NRTI is generally a more effective treatment than taking either independently.
Pharmaceutical developers therefore have designed drugs to inhibit the enzyme and thus interfere
with the replication of the virus. These drugs act by preventing cleavage of HIV viral polyproteins
into active proteins, which occurs during the process by which HIV normally replicates. The drugs
bind to the enzyme’s active site, blocking cleavage of the polyprotein. The goal of the protease
inhibitor thus is to stop the protease from helping to assemble a new virus by preventing
(sometimes referred to as gumming up) protease from cutting long chains of proteins into shorter
pieces that HIV needs to assemble a new virus. They interrupt the way HIV uses a healthy cell to
make more viruses.
PROTEASE
PROTEASE
PROTEASE
INHIBITOR
HIV PROTEIN
SHORTER CHAIN
OF HIV PROTEIN
Individual
proteins that
make new
HIV particles
Individual
enzymes that
help build new
HIV particles
Protease Inhibitors are
drugs
that
resemble
pieces of the protein chain
that protease normally
cuts. By “gumming up”
the protease “scissors,”
HIV protease inhibitors
prevent
protease
from
cutting long chains of
proteins and enzymes into
the shorter pieces that
HIV needs to make new
copies of itself.
Resistance to protease
inhibitors develop when small changes occur to the structure of HIV’s protease enzyme. Protease
Inhibitors fit into a “pocket-like” area on HIV’s protease enzyme. If the drugs cannot fit in these
pockets then the strain is resistant to the drug.
Resistance to one protease inhibitor often hastens resistance to many others. The family of protease
inhibitors is quite susceptible to cross-resistance. This serves as a major concern for physicians
when prescribing PIs. If a patient does not follow their dosing regimen they very well may develop
resistance to PIs. This may mean that in the future if more potent and effective PIs are produced a
patient that has developed a previous resistance to PIs may not be able to benefit from these newer
PIs.
Abbott Pharmaceutical (NYSE: ABT) is the leader in the protease inhibitor market with
Kaletra®. It’s a single capsule combination of lopinavir and ritonavir. Kaletra® has had very
favorable testing results when compared to other antiretroviral drugs. Its ability to suppress viral
loads exceeded that of Viracept®. At 40 weeks, 79% of patients on Kaletra® had undetectable viral
loads while 64% of patients on Viracept® had undetectable levels. In long term studies Kaletra®
has shown amazing durability as well. In mid 2003 Kaletra® was leading the way with 32% of new
PI subscriptions and 34% of total PI subscriptions. Currently Kaletra® is losing ground to some of
the newer protease inhibitors on the market. These newer PIs include Bristol-Myers Squibb’s
Reyataz® and GlaxoSmithKline/Vertex’s Lexiva®. Kaletra® achieved sales of $896 million
(+19%) in fiscal year 2004.
GlaxoSmithKline/Vertex’s (NYSE: GSK, NasdaqNM: VRTX) Lexiva® is poised to take a portion
of the protease inhibitor market. Its low pill burden and flexibility in dosing make it very appealing
for many patients. Lexiva® can be taken in three different dosing regimens with the maximum
number of doses being two per day. GlaxoSmithKline’s protease inhibitors Lexiva® and Agenerase®
achieved combined sales of $120.5 million (+80%) in 2004.
Bristol-Myers Squibb’s (NYSE: BMY) Reyataz® has some major advantages over current
protease inhibitors. It is shown to be 2-9 times more potent than most protease inhibitors.
Reyataz® is effective against resistant strains of HIV; even strains that have become resistant to
other protease inhibitors. Reyataz® achieved sales of $414 million in 2004.
23
APPROVED PIS
Crixivan® (indinavir) – Merck & Co (NYSE: MRK)
Crixivan® had been considered the standard of care in HIV therapy but is slowly losing ground to
newer PIs and NNRTIs. Crixivan® was launched in March of 1996. There are two major drawbacks
to Crixivan® use: patients must take it three times a day with a lot of water on an empty stomach
or with specific small snacks, or put themselves at risk for kidney stones; and if patients become
resistant to the drug, they may develop resistance to other protease inhibitors at the same time.
This is known as cross-resistance.
Indinavir may also cause upset stomach, bloating or skin rash. In rare cases anemia may occur. As
of November 2004 no generic versions of indinavir have been approved by the World Health
Organization although several are manufactured. There is evidence to suggest that indinavir is able
to penetrate the blood brain barrier and thus fight HIV throughout the body. Studies using indinavir
as the only PI in a triple-drug cocktail combination have shown poor results. Crixivan® achieved
sales of $255 million (-10%) in fiscal year 2004.32
Viracept® (nelfinavir) – Pfizer (Agouron Unit) (NYSE: PFE)
Viracept® was approved by the FDA in March of 1997. Viracept® was originally dosed as three 250
mg capsules three times a day. In 1999 the FDA approved twice daily dosing of five pills at a time
at 1250 mg per dose. Viracept® does not have major problems with cross-resistance allowing for
future treatment with other protease inhibitors. Viracept® can be given to children that are two
years of age or older. The side effects of nelfinavir do not appear to be very serious; they include
diarrhea, weakness, headache, nausea and abdominal pain.
Generic versions of nelfinavir include Nelvir (Cipla), Nelfin (Genixpharma), Nelvex (Aurobindo), and
Nefavir (Ranbaxy). Viracept® achieved sales of $259 million (-23%) in 2003.33
Kaletra® (lopinavir + ritonavir) – Abbott Laboratories (NYSE: ABT)
Kaletra® was granted accelerated FDA approval in September 2000. Kaletra® is able to provide
protection in patients that have developed resistance to other protease inhibitors. The normal dose
of Kaletra® is three capsules twice a day. Each capsule consists of 133 mg of lopinavir and 33 mg
of ritonavir. Kaletra® also comes in liquid form and should be taken with food.
Side effects of Kaletra® include diarrhea, fatigue, headache and nausea. Kaletra® may increase the
amount of fat in the blood potentially leading to problems with the heart or pancreas. Kaletra® is
also approved for use in children. Kaletra® regimens appear to be more potent than regimens
containing other PIs. Studies have shown that Kaletra® can be affective as salvage therapy for
patients who have taken multiple PIs. Kaletra® achieved sales of $896 million (+19%) in 2004.34
Agenerase® (amprenavir) – GlaxoSmithKline/Vertex (NYSE: GSK, NasdaqNM: VRTX)
Agenerase® was approved by the FDA in April 1999. Agenerase® is taken twice a day orally.
Patients used to take eight 150-mg capsules at a time for a total dosage 1200 mg. The 150 mg
capsules are no longer available but amprenavir is still available in 50-mg capsules. Amprenavir is
usually taken with ritonavir. It comes in capsule form or liquid form.
The side effects of Agenerase® include those common to most PIs: nausea, diarrhea, vomiting,
rash, numbness around the mouth and abdominal pain.
A small percentage of patients
(approximately 1%) get serious skin reactions including Stevens-Johnson syndrome. Amprenavir is
not recommended for first line therapy because of its poor results in clinical trials. Amprenavir has
one of the highest pill regimens of the PIs; this may make it unattractive to patients and doctors
alike. GlaxoSmithKline’s protease inhibitors Agenerase® and Lexiva® achieved combined sales of
$120.5 million (+80%) in 2004.35
32
33
34
35
Merck company website: www.merck.com
Pfizer company website: www.pfizer.com
Abbott company website: www.abbott.com
GlaxoSmithKline company website: www.gsk.com
24
Norvir® (ritonavir) – Abbott Laboratories (NYSE: ABT)
Norvir® was approved by the FDA in March 1996 and is very rarely used as a protease inhibitor
anymore. It is typically used as a boost for other protease inhibitors. Ritonavir is able to raise the
blood levels of other drugs because it slows down the liver. The normal dose of ritonavir is 600 mg
twice a day and the capsules, which are taken orally, are 100 mg a piece. Ritonavir should be taken
with meals. When taken as a boost, ritonavir’s dosing will change. Ritonavir can also be taken as a
liquid.
Ritonavir’s side effects include nausea, vomiting, gas and diarrhea. It may also cause tingling or
numbness around the mouth. These side effects caused approximately one third of patients to stop
taking ritonavir. There is a generic version of ritonavir called Ritovir manufactured by Hetero/Genix.
Ritonavir appears to have a high anti-malarial effect making it very appealing to areas facing both
HIV and Malaria epidemics.36
Fortovase®/Invirase® (saquinavir) – Roche Pharmaceuticals (OTC: RHHBY.PK)
Invirase® (saquinavir in hard gel cap form), the first protease inhibitor, was approved by the FDA in
December of 1995. Fortovase®(saquinavir in soft gel cap form), was approved by the FDA in
November 1997. Because of its poor bioavailability, Invirase® was phased out and the focus was
shifted to Fortovase®, the soft gel cap formulation. 1200 mg of Fortovase® are taken 3 times a
day. Each capsule is 200 mg so the patient will take six at a time. Fortovase® should be taken with
high-fat, high-protein food. Saquinavir is commonly boosted with ritonavir and a 1000 mg
Invirase® (preferred when boosted with ritonavir) dose combined with 100 mg ritonavir dose was
approved by the FDA in 2003. The side effects of saquinvair are mild. They include nausea,
diarrhea, upset stomach and heartburn. Saquinavir is currently being tested in a twice daily
regimen.37
Reyataz® (atazanavir) - Bristol-Myers Squibb (NYSE: BMY)
Reyataz®’s active ingredient is atazanavir which was formerly known as BMS-232632. Reyataz®
was approved by the FDA in June 2003. Reyataz®, unlike other protease inhibitors, does not lead to
increases in blood fats. Physicians prescribe Reyataz® for patients with high cholesterol,
triglycerides, or any other risk factors for heart disease.
A major benefit of atazanavir is that it can provide high enough blood levels to control HIV that may
already be resistant to other protease inhibitors. Atazanavir is usually a 400 milligram capsule taken
orally once a day. For patients who have taken protease inhibitors before, the dose may be reduced
to 300 mg along with 100 mg booster of ritonavir (Norvir®). Patients must take multiple capsules
when taking atazanavir because it comes in capsules of 100 mg, 150 mg and 200 mg. About 10%
of the patients taking atazanavir are diagnosed with jaundice. Atazanavir may not increase the
long-term risk of heart disease like other protease inhibitors because it does not increase the levels
of fat or sugar in the blood. Side effects include possible changes in heart rhythm as well as
common side effects associated with anti HIV drugs such as nausea, headache, rash, stomach pain,
vomiting, diarrhea, tingling in hands or feet, and depression. Reyataz® achieved sales of $414
million in 2004.38
Lexiva® (fosamprenavir) – GlaxoSmithKline (NYSE: GSK)
Lexiva® (known as Telzir® in Europe) was approved by the FDA in October 2003. Fosamprenavir,
the active ingredient in Lexiva®, was formerly known as GW433908, or just 908. Fosamprenavir
(pro-drug) is broken down in the patient’s body to produce an active drug known as amprenavir.
Fosamprenavir is not active against HIV; it becomes active against HIV when it becomes
amprenavir. Fosamprenavir is promising because it might not be cross-resistant with other protease
inhibitors. The normal dosage of Fosamprenavir is two 700 milligram tablets taken orally twice daily.
Lexiva® is also approved to be combined with ritonavir.
36
37
38
Abbott Laboratories company website: www.abbott.com
Roche company website: www.roche.com
Bristol-Meyers Squibb company website: www.bms.com
25
Side effects include those associated with anti-HIV drugs including nausea, diarrhea, vomiting, rash,
and headache. Some patients experienced numbness around the mouth, and abdominal pain. A
small percentage (less than 1%) of patients may develop serious skin reactions; some may develop
Stevens-Johnson syndrome. Fosamprenavir, like other protease inhibitors, can increase a patient’s
blood fat. The increase may not be as severe as many other protease inhibitors. Studies have
shown that fosamprenavir may work better if it is taken in association with the NRTI abacavir.
GlaxoSmithKline’s protease inhibitors Lexiva® and Agenerase® achieved combined sales of $120.5
million (+80%) in 2004.39
PI’S IN DEVELOPMENT
GW640385 – GlaxoSmithKline/Vertex (NYSE: GSK, NasdaqNM: VRTX)
GW640385 is currently in Phase II trials. GW640385 has shown to be effective against the wild type
virus as well as appear to be able to prevent HIV resistance better than current protease inhibitors.
GW640385 is also able to be taken in lower doses which may translate into fewer side effects.
Presently it will probably be boosted with ritonavir.40
Tipranavir (PNU-140690)- Boehringer Ingelheim
Tipranavir also known as PNU-140690 is a new HIV protease inhibitor. Early indications are that it
works against HIV that is currently resistant to other protease inhibitors. It is in Phase III trials and
is being combined with ritonavir. Currently it is being used as a twice daily dosage but is
experiencing a high level of common side effects such as vomiting and nausea. Tipranavir is
currently being tested in treatment-naïve patients. Boehringer Ingelheim submitted a New Drug
Application (NDA) for tipranavir in October of 2004 and is looking for accelerated approval of the
drug asking for a priority, six month review of the NDA.41
TMC 114 – Johnson & Johnson (Tibotec Unit) (NYSE: JNJ)
TMC 114, in Phase II studies, shows promise and is able to produce very rapid drops in viral load.
Boosting TMC 114 with ritonavir is currently being tested and has shown strong efficacy in viral load
reduction. Because of TMC 114’s unique structure it may be effective against strains of the HIV virus
that are resistant to other protease inhibitors. It is a flexible molecule that can adapt itself to the
changing shape of the mutant virus. The goal is for the drug to be taken as a single pill once daily;
however, the proper dosing has not yet been reported. TMC 114’s side effects are similar to many
other protease inhibitors including: diarrhea, vomiting, nausea, headache, and skin disorders.42
PL-100 – Procyon Biopharma Inc. (Toronto: PBP.TO)
Although in early stages, in-vitro tests of PL-100 show the drug as very effective against strains of
HIV that are resistant to current protease inhibitors. PL-100 has not been tested on humans or
animals so there is currently no safety data available. Procyon expects to conduct human trials
within the next year.43
39
40
41
42
43
GlaxoSmithKline company website: www.gsk.com
Ibid
Boehringer-Ingelheim company website. For more information please see: www.boehringer-ingelheim.com
Johnson & Johnson company website: www.jnj.com
Procyon Biopharma, Inc. company website. For further information please visit: www.procyonbiopharma.com
26
Protease Inhibitors
Brand
Name
Generic
Chemical
Name
Current
Phase
FDA
Approval
Manufacturer
Sales in
Millions
2004
% Change
in Sales
Crixivan®
indinavir
MK639
Approved
Mar-96
Merck and Co.
$ 255 M
Viracept®
nelfinavir
AG1343
Approved
Mar-97
Pfizer (Agouron)
$ 259 M*
-10%
-23%
Kaletra®
lopinavir +
ritonavir
AB378r
Approved
Sep-00
Abbott
$ 896 M
19.20%
Agenerase®
amprenavir
VX-478
Approved
Apr-99
GlaxoSmithKline/Vertex
$ 120.5 M
(Agenerase
and Lexiva)
80%
(Agenerase
and Lexiva)
Norvir®
ritonavir
ABT-538
Approved
Mar-96
Abbott
N/A
N/A
Fortavase®/
Invirase®
saquinavir
Ro 31-8959
Approved
Dec-95
Roche
N/A
N/A
Reyataz®
atazanavir
BMS-232632
Approved
Jun-03
Bristol-Myers Squibb
$ 414 M
N/A
Lexiva®
fosamprenavir
GW433908
Approved
Oct-03
GlaxoSmithKline
$ 120.5 M
(Agenerase
and Lexiva)
80%
(Agenerase
and Lexiva)
GW640385
Phase II
GlaxoSmithKline/Vertex
Tipranavir
PNU-140690
Phase III
Boehringer Ingelheim
TMC114
Phase II
Johnson & Johnson
PL-100
Preclinical
Procyon Biopharma
*2003 sales
27
7.
NEW DIRECTIONS IN TREATMENT
With drug resistance undermining the effectiveness of available antiretroviral drugs, AIDS clinicians
are looking toward therapies to expand treatment options and to strengthen the weakening immune
response associated with AIDS. These alternative methods of attacking HIV include: Entry
Inhibitors, which work by preventing HIV from attaching to and entering host cells; and immunebased therapies as a means of correcting immune deficiencies and strengthening the effects of drug
therapy.
Many physicians hope this area can be used as adjunctive therapy combined with existing HAART
(Highly Active Anti-Retroviral Therapy) to reduce side effects, enhance the efficacy of existing
treatments and delay the progression of the HIV virus. Many of these drugs are still in development
and represent a new direction for physicians and patients alike to attack HIV’s ability to attach to
the human cell and further along in the infection to prevent the destruction of the immune system.
Despite all of the developments and advancements in the field of antiretroviral therapy including
fighting transcription and fusion prevention there are still many problems that exist. Viral reservoirs
(brain, spinal fluid), development of drug resistance and the toxic effects seen from many
contemporary drugs all threaten the current antiretroviral regimens. A large majority of HIVpatients are infected with viruses that are currently resistant to one or more classes of antiretroviral
agents. Through these concerns there has a grown a desire to find more novel approaches to
fighting HIV.
7.1 HIV ENTRY INHIBITORS
Some antiviral treatments attempt to inhibit viral attachment and thus prevent HIV from entering
the human cell. Certain parts of the HIV virus attach to certain areas on the human cell. Scientists
hope that by targeting these particular sites on both the human cell and the HIV virus they will be
able to prevent infection. Most entry inhibitors must be taken by injection because digestive acids
will break them down. Many of the pipeline drugs in this category attack the CCR5 receptor. The
CCR5 receptor helps direct immune cells to damaged or diseased areas of the body. This is how HIV
enters and infects T cells. There is a small percentage approximately 10 percent of people of
European decent that have a naturally occurring defect in their CCR5 receptor. In patients with this
defect HIV is unable to progress at the same rate as in someone without this genetic defect. These
products are known as CCR5 receptor antagonists.
Roche Pharmaceuticals (OTC: RHHBY.PK) and Trimeris, Inc. (NasdaqNM: TRMS) are the
leaders in the HIV fusion inhibitor category with their leading product Fuzeon®. Fuzeon® has had a
few road blocks on the way - the most important being its difficulty in dosing. Doctors have been
reluctant to prescribe Fuzeon® because of their fear that patients will not be compliant with the
dosing. The rate of new prescriptions for Fuzeon® dropped approximately 50 percent in 2004,
however, Fuzeon® did still achieve worldwide sales of $135 million (+27%). Currently there are
multiple fusion inhibitors in the product pipeline.
APPROVED ENTRY INHIBITORS
Fuzeon® (enfuvirtide) – Roche/Trimeris (OTC: RHHBY.PK, NasdaqNM: TRMS) – Fusion
Inhibitor
Enfuvirtide, also called T-20, is the active ingredient in Fuzeon®, a drug that was granted
accelerated approval by the FDA in March 2003. Enfuvirtide is the first of a new kind of drug known
as “fusion inhibitors”. Enfuvirtide prevents HIV from fusing with healthy cells thus the HIV cannot
infect the cell. Enfuvirtide is administered through injection twice a day and is most likely to be
used by people who have few choices of antiviral medications in pill form. Enfuvirtide is most likely
to be taken with other anti-HIV drugs due to its inability to prevent HIV resistance when taken
alone. Enfuvirtide also shows no signs of cross resistance with any other antiviral drugs. Side
effects include skin irritation, swelling or itchiness at point of injection as well as headaches, pain
and numbness in feet or legs, dizziness, and loss of sleep. Enfuvirtide does not seem to interact
28
harshly with any other anti-HIV drugs. Data that was presented at the 15th International AIDS
Conference showed Fuzeon® combined with conventional antiretroviral therapy was very effective.
After two years, the proportion of patients with the virus reduced to undetectable levels was 26
percent. This was twice as many as those on standard treatment.
FUZEON®
gp41
gp41
Unlike existing AIDS drugs that work
inside the cell to target viral enzymes
involved in the replication of the virus,
Fuzeon® inhibits fusion of HIV with
host cells before the virus enters the
cell and begins its replication process.
It targets the cycle when HIV attaches
itself to T-cell (site gp41 molecule on
the virus). Thus, the Fuzeon® blocks
HIV viral fusion by interfering with
certain structural arrangements with
gp41 that is required for HIV to fuse to
and enter a host cell. Fuzeon® is likely
to be reserved for patients who have
failed two antiviral regimens.44
ENTRY INHIBITORS IN DEVELOPMENT
AMD070 – AnorMed Inc. (Toronto: AOM.TO)
AMD070, currently in Phase I/II trials, works by blocking the CXCR4 receptor on CD4 T-cells to
prevent or inhibit HIV fusion. AMD070 is an experimental anti-HIV treatment which belongs to the
new class of drugs known as CXCR4 inhibitors. It showed a suitable toxicity profile for oral dosing,
however, AMD070 does have its problems. It is not active against the more common HIV strain
which uses the CCR5 co-receptor. Since CXCR4 is expressed on many more cell types adverse
affects associated with AMD070 may be greater.45
GW873140 – GlaxoSmithKline/ Ono Pharmaceutical (NYSE: GSK, OTC: OPHLF.PK)
Currently in Phase II studies, GW873140 appears to bind very tightly to CCR5 receptors on the cell
surface and appears to have minor side effects including nausea, diarrhea, and mild cramping.
Initial reports indicated that GW873140 has minimal CNS penetration. The developers are hoping
that the drug can be taken once daily. GlaxoSmithKline expects to file for a new drug application in
2007.46
PRO 140 & PRO 542 – Progenics (NasdaqNM: PGNX)
Like many entry inhibitors PRO 140 & PRO 542 work by preventing fusion on the surface of CD4
cells. PRO 140 is a humanized monoclonal antibody designed to inhibit virus-cell binding. It is a
monoclonal antibody to CCR5, one of the receptors needed for HIV to enter the human cell. PRO
140 is designed to bind to a portion of the CCR5 receptor blocking HIV entry while having no
apparent effect on the normal function of CCR5. PRO 140 was shown to be effective at protecting
both primary T-cells and macrophages, the immune system cells that are the major targets for HIV
infection. In a 2000 study, PRO 140 potently blocked each of 17 HIV isolates that are typical to
those associated with person-to-person transmission of the virus and with the asymptomatic phase
of infection. In February 2002 Progenics selected a humanized version of the PRO 140 antibody for
use in clinical testing.
44
45
46
Roche and Trimeris company websites. For more information please visit: www.roche.com and www.trimeris.com
AnorMED, Inc. company website. For more information please visit: www.anormed.com
GlaxoSmithKline company website: www.gsk.com
29
PRO 542 is an anti-body like product that neutralized HIV by preventing it from attaching to the
CD4 receptor on the surface of immune system cells. PRO 542 appears to be most effective in late
stage disease. There are some concerns over the high dosing requirements of PRO 542 which in a
current study includes 3 injections per week for 3 weeks. PRO 542 may be effective in children that
are unwilling or unable to take tablets and may also have value as a prophylaxis treatment.
Progenics Pharmaceuticals has announced that the target population for PRO 542 would be patients
with advanced disease. In September 2002, Progenics announced results of a Phase II clinical trial
in which twelve treatment-experienced patients received a single dose of PRO 542 and their viral
concentrations were reduced 60%-80% on average. PRO 140 is in preclinical trials and PRO 542 is
in Phase II trials.47
Schering-D (SCH-D) - Schering Plough (NYSE: SGP)
SCH-D works by blocking the CCR5 receptor on CD4 cells and has very few side effects. It has
better in vitro potency as well as better bioavailability than Schering’s previous entry inhibitor SCHC. No significant toxicity has been seen in SCH-D either. Currently SCH-D’s in vitro effects appear to
be correlated with solid in vivo activity. Resistance to SCH-D appears very slowly if at all, leading
researchers to believe it may have long term efficacy. It is currently in Phase II trials.48
TNX-355 – Tanox, Inc./Biogen Idec (NasdaqNM: TNOX, NasdaqNM: BIIB)
Like most other entry inhibitors, TNX-355 blocks the CD4 receptors. Upon entering Phase II trials it
has not shown any significant side effects. TNX-355 is a genetically engineered drug which is also
known as a "monoclonal antibody." Treatment is administered in one of two ways: intravenous
infusion or a twice-monthly injection. TNX-355 may be used in salvage therapy or for post-exposure
prophylaxis. TNX-355 does not appear to suppress immune function or deplete CD-4 cell counts.49
Maraviroc (UK-427,857) – Pfizer (NYSE: PFE)
Maraviroc is a chemokine receptor antagonist currently in Phase II/III clinical trials. Like many other
entry inhibitor drugs in the pipeline Maraviroc blocks the CCR5 receptor. Maraviroc is thought to be
30 times more potent than ritonavir (Norvir®), and resistance to Maraviroc seems to appear slowly.
In small scale studies there have been no significant side effects seen.50
SP01A – Samaritan Pharmaceuticals (AMEX: LIV)
SP01A is currently in Phase II trials and has demonstrated the ability to significantly reduce viral
load in patients infected with the HIV virus. SP01A comes in capsule form and is taken twice a day.
Resistance does not appear to develop to SP01A and it will be able to be taken by patients at all
stages of anti-HIV therapy. SP01A interferes with HIV’s regulation mechanisms preventing it from
entering and infecting healthy cells.51
47
Progenics Pharmaceuticals, Inc. company website: www.progenics.com and
Schering-Plough company website: www.sch-plough.com
Tanox, Inc. company website: www.tanox.com
50
Pfizer company website: www.pfizer.com
51
Samaritan Pharmaceuticals company website and AIDS Education Global Information System websites, found at
www.samaritanpharma.com and www.aegis.org, respectively
48
49
30
7.2 IMMUNE-BASED THERAPIES AND OTHER ADJUNCT APPROACHES
The immune system plays an important role in two important aspects of the HIV infection:
determining the baseline concentration of virus in the body and delaying disease progression.
Immune modulators are designed to help the efforts of one or more of the so-called armies of the
immune system: antibodies; natural killer cells; killer T-cells (also known as “cytotoxic T-cells”,
“CD8 cells”, or “CTLs”); and helper T-cells (also called “CD4 cells”). However, since latent virus
remains present in many cells and lymphoid tissues of the body (and virtually undetected in the
blood), these cells can persist for a long time, and virus lurking within them can rekindle active HIV
infection. When and if these cells become active, they can begin producing viruses. This reservoir
of resting cells is believed to be one of the major barriers to completely eliminating HIV from a
person’s body. It is very likely that the next generation of effective treatments will involve
converting this latent virus into active cells, so that it can be “flushed out” and confronted. That is,
once activated, these cells would be subjected to the immune system, immune-based therapies,
antiviral drugs and other HIV treatments.
IMMUNE-BASED THERAPIES IN DEVELOPMENT
Proleukin® (interleukin-2, IL-2) – Chiron Corporation (NasdaqNM: CHIR)
Proleukin® is a recombinant form of interleukin-2 (IL-2), a naturally occurring chemical called a
cytokine, produced by certain cells of the immune system. Cytokines are your body’s own chemical
messengers that can be manipulated to increase the immune response to HIV. Each cytokine can
carry a different message telling your body how to deal with cells. T-helper cells, a type of white
blood cell, produce the protein IL-2 when they are stimulated by an infection. IL-2 is known as an
immune modulator and serves as a catalyst by multiplying and maturing infection-fighting cells.
Interleukin-2 is approved by the FDA to fight cancer but is not yet approved for HIV disease. IL-2
works by increasing the number of CD4+ cells through stimulation of the immune system. IL-2 does
not recover lost types of T-cells but is able to make copies of existing ones. IL-2 shows promise in
increasing T-cells counts especially when it is taken either in intravenous infusion form or as a
twice-daily subcutaneous injection every day for 5 days, once every 8 weeks. As the T-count
increases the cycles may occur less frequently. IL-2 must be taken in conjunction with other
antiviral drugs. The most prevalent side effect is capillary leak syndrome which causes weight gain,
swelling, low blood pressure, and other problems. IL-2 may also cause mood changes such as
irritability and depression. At lower doses IL-2 may reduce the number of neutrophils, a type of
infection-fighting cell, and may affect the thyroid. There appears to be no major side effects of IL2, and it will soon enter in Phase III trials. Proleukin® may also be effective at decreasing or
eliminating hidden pools of the virus. Currently companies such as Amgen Inc. (NasdaqNM:
AMGN) (IL-15), Biotech Inflection Point (IL-7), and Regeneron Pharmaceuticals Inc.
(NasdaqNM: REGN) (IL-4, IL-13 trap) are developing other methods for using cytokines to help
fight HIV infection most of which are in Pre-clinical to Phase I studies.52
There are multiple immune-based therapies that are currently in production and development:
•
•
•
52
53
54
Bay 50-4798 (interleukin-2) by Bayer Corporation (NYSE: BAY) is in Phase I/II trials. It
consists of a recombinant form of IL-2. However, Bay 50-4798 does not affect other immune
cells like IL-2 does which may reduce the risk of side effects. Bay 50-4798 may have to be
injected twice a day.53
Multikine® by Cel-Sci Corporation (AMEX: CVM) is currently in Phase I/II human trials for
the treatment of cancer; Multikine® is a combination of several different cytokines. These
cytokines include interleukins, interferons, chemokines and colony-stimulating factors.
Multikine® appears to be non-toxic and is able to boost patient’s immune systems. Cel-Sci
hopes to develop Multikine® for adjuvant treatment in HIV infected individuals.54
Ampligen® by Hemispherx Biopharma (AMEX: HEB), in Phase II trials, is a synthetic RNA
molecule that is able to stimulate the immune system by encouraging it to produce interferon
Chiron Corporation company website: www.chiron.com
Bayer Corporation company website: www.bayer.com
Cel-Sci Corporation company website: www.cel-sci.com
31
•
•
which activates a cell defenses against viruses. It has minimal side effects including flu-like
symptoms, chest tightness, transient neutropenia and malaise. Ampligen® is available as oral
tablets known as Oragens. Oragens are currently in pre-clinical studies.55
Immunitin™ (HE2000) by Hollis-Eden Pharmaceuticals (NasdaqNM: HEPH) targets and
attempts to strengthen the “humoral” immune response which is responsible for producing
antibodies and therefore fighting HIV infection. This may help reestablish immune system
balance when it is in disrepair. Immunitin™ has shown activity against malaria and tuberculosis
as well. HE2000 is currently in Phase I/II trials.56
MDX010 by Medarex Inc. (NasdaqNM: MEDX) is a fully human antibody that fights the
CTLA receptor. CTLA-4 is blamed for the suppressed immune response that is associated with
HIV infection. By blocking this suppressive activity MDX010 may enhance the anti-HIV immune
response and thus allow the body to fight HIV more effectively. It is currently in Phase I/II
testing.57
55
Hemispherx Biopharma, Inc. company website: www.hemispherx.net and the Podell and King Medical Practice
website: www.drpodell.org
Hollis-Eden Pharmaceuticals company website: www.holliseden.com
57
Medarex, Inc. company website: www.medarex.com
56
32
7.3 ALTERNATIVE APPROACHES
With no end to the AIDS epidemic in sight scientists and drug manufacturers alike have begun
searching for alternative methods to turn the tides on the HIV virus. Because of HIV’s ability to
develop resistance and mutate, the current drugs have been able to only partially stem the tide
against HIV’s rapid reproduction and infection. Scientists have begun to think “outside the box”
when fighting HIV and AIDS. Currently pharmaceutical companies are developing multiple ways of
attacking HIV from filtering the blood through a dialysis machine to attacking the HIV virus’s inner
core. Innovative thinking will soon open the door to more novel and effective ways of attacking HIV.
The Hemopurifier - Aethlon Medical (OTC BB: AEMD.OB)
Researchers from Aethlon Medical have developed a potentially promising extracorporeal entry
inhibitor, the Hemopurifier (HIV dialysis). The Hemopurifier, by decreasing viral load, appears to
have a number of attributes necessary for a globally practical therapy for HIV, both as a conjunctive
and salvage therapy. And by removing mutant strains, could extend the life of currently approved
drugs and could represent a valuable lifecycle management strategy. The Hemopurifier is able to
clear infectious HIV, gp120 and other related toxins before infection occurs. Also, since the
Hemopurifier does not cause cross-resistance, and given the new government guidelines that
encourage the delay of initial drug regimens, it may be utilized as a first line therapy, reducing viral
load and delaying the need to start antiviral therapy. Aethlon Medical’s dialysis approach could also
represent an important adjunct therapy for current dialysis patients that are co-infected with HIV
(estimated to be a significant percent of the current kidney dialysis population). Aethlon also has
plans to use the Hemopurifier™ as a treatment countermeasure against drug and vaccine resistant
biological weapons. In one hour of treatment The Hemopurifier™ has cleared 90% of the toxic
protein gp-120, which depletes healthy immune cells.58 Aethlon scientists are also researching the
capability of the Hemopurifier to regulate the overproduction of Cytokines, which could improve the
treatment outcomes of both infectious and autoimmune diseases.
STANDARD DIALYSIS CARTRIDGE
Antibodies & Antisense DNA
Are added to cartridge
Blood
containing HIV
virus comes
into the dialysis
HIV Antibodies +
Antisense DNA
Blood with
reduced HIV load
comes out
Hollow fibers
Captured HIV
The Hemopurifier, by removing
mutant
strains
that
cause
resistances, could extend the life
of currently approved drugs, and
represent a valuable lifecycle
management strategy for patients
and pharmaceutical companies.
Free HIV virus
L-870,810 – Merck Pharmaceutical (NYSE: MRK) -Integrase Inhibitor
Scientists hope to target HIV by preventing the virus from integrating itself into the genetic code of
an infected cell. The reverse transcriptase enzyme changes HIV’s genetic code from single strand to
double strand after this process is complete HIV integrates itself in the genetic code of the infected
cell. When the HIV genetic code is read it begins producing new viruses. If the integration was
stopped using drugs, the HIV virus would not be able to reproduce itself. Many pharmaceutical
58
Aethlon company website and AEGIS (AIDS Education Global Information System) Please see www.aethlonmedical.com
and www.aegis.com for more information
33
companies are currently researching integrase inhibitors including using DNA proteins and medicinal
plants.
Both in vitro and in vivo studies showed that resistance to L-870,810 was slow to develop. If the
virus did develop resistance it was severely hindered in its ability to reproduce. The side effects of
L-870,810 appear to be minimal. It is in Phase I clinical trails. Merck’s current restructuring has
hindered production of L-870,810. There are multiple integrase inhibitors currently in the preclinical
stage.59
PA-457 – VI Technologies (NasdaqNM: VITX) - Maturation Inhibitor
Virus maturation occurs during the last stages of HIV reproduction. After the infected cell releases
the virus it begins processing viral proteins in order to become infectious. By inhibiting the
maturation process the new virus is unable to infect new cells.
Currently in Phase I clinical trials, PA-457 is the first maturation inhibitor. The drug works by
inhibiting the development of HIV’s internal structures in a new virus. PA-457 warps the shape and
activity of newly produced HIV capsids during Gag processing. This inhibits the replication of new
viruses. PA-457 is entering Phase II studies and data from Phase I studies showed very few side
effects. PA-457 will probably be taken orally once-a-day. There are multiple maturation inhibitors
currently in the preclinical stage.60
Azodicarbonamide (ADA) – Hubriphar (H-Phar) – Zinc Finger Inhibitor
ADA is the first zinc finger inhibitor, and it is currently in Phase I/II trials. Zinc fingers refer to the
chain of amino acids that hold the nucleocapsid or HIV inner core together. They are involved in
binding and packaging viral DNA. The purpose of zinc finger inhibitors (or zinc ejectors) is to break
apart and destroy these structures preventing the virus from functioning properly. The HIV core
does not mutate so drugs targeting them could last a long time, however, zinc fingers are not only
used by the HIV virus and destroying all zinc fingers in someone’s body could cause serious side
effects. Some of the side effects that have been seen in patients taking ADA include kidney pain
and urine abnormalities. ADA may be re-formulated so that it can be taken in smaller doses to
reduce side effects.61
HGTV43 - Enzo Biochem Inc. (NYSE: ENZ) – Antisense Drug
Antisense drugs work by mirroring part of the HIV genetic code. They are short pieces of nucleic
acid that bind to specific parts of HIV’s genetic code. The drug locks on to the HIV virus and
prevents it from functioning properly. HGTV43 has had good in vitro results and it is beginning
Phase II trials. Solid efficacy has been shown in Phase I trials, and the drug seems to be well
tolerated.62
VRX496 – VIRxSYS – Gene Therapy
Gene therapy, as opposed to other anti-HIV techniques, targets an earlier stage of virus
development. It interferes with the genetic processes by which HIV is made.
HIV can be treated as a genetic disorder because it takes its own RNA and converts it to DNA then
inserts it into the DNA of the infected cell. Through gene therapy scientists may be able to target
the HIV genes in infected cells correcting it as if it were a genetic disorder.
VRX496 is genetically modified to infect T-cells and attacks HIV's genetic code. It is in Phase I
studies. VRX496 can turn HIV against itself and is able to “cut” HIV’s genetic code. VRX496 may
serve as an alternative to HAART. It has been demonstrated to inhibit HIV replication by over 99
percent.63
59
60
61
62
63
Merk company website: www.merck.com
Vitex company website: www.vitechnologies.com
H-Phar Pharmaceuticals company website: www.h-phar.com
Enzo Biochem company website: www.enzobiochem.com
Virxsys company webpage: www.virxsys.com
34
New Directions: Entry Inhibitors, Immune-Based Therapy and Other Adjunct
Approaches
Brand Name
Fuzeon®
Product
Chemical
Name
Current Phase
Manufacturer
Sales
in
Millions
2004
$ 135 M
Entry Inhibitor
T-20
Approved (Mar-03)
Roche and Trimeris
AnorMed
Entry Inhibitor
AMD070
Phase I/II
Entry Inhibitor
GW873140
Phase II
GlaxoSmithKline
Entry Inhibitor
PRO 140
Preclinical
Progenics
Entry Inhibitor
PRO 542
Phase II
Progenics
Entry Inhibitor
SCH-D
Phase II
Schering Plough
Entry Inhibitor
TNX-355
Phase II
Tanox
Entry Inhibitor
SP01A
Phase II
Maraviroc
Entry Inhibitor
UK-427,857
Phase II/III
Samaritan
Pharmaceuticals
Pfizer
Proleukin®
Immune-Based
interleukin-2
Phase II/III
Chiron
Multikine®
Immune-Based
Immune-Based
Bay 50-4798
Phase I/II
Cel-Sci Corp
Phase I/II
Bayer
Phase II
HemiSpherx Biopharma
Ampligen®
Immune-Based
Immunitin
Immune-Based
HE2000
Phase I/II
Hollis-Eden
Immune-Based
MDX010
Phase II
Medarex
Preclinical
Aethlon Medical
Integrase Inhibitor
L-870,810
Phase I
Merck
Maturation Inhibitor
PA-457
Phase I
Panacos
Zinc Finger
Inhibitor
Antisense Drug
ADA
Phase I/II
Hubriphar
HGTV43
Phase I
Enzo
Gene Therapy
VRX496
Phase I
VIRxSYS
Hemopurifier™
Adjunct Therapy
35
8.
VACCINES
HOW A VACCINE WOULD STIMULATE ANTIBODIES
1
2
3
Helper Tcells
HT
antibodies
4
B
HIV
MB
B
Memory
B-cells
HIV particles
B-cells
Plasma cells
P
5
P
antibodies
1.
An HIV vaccine would alert the body that the virus is present and stimulate immune cells,
known as B cells, into making disease-fighting antibodies.
2.
Once the immune system detects the infection, B cells bind to the virus and digest it.
3.
Once it's digested, the B cells display pieces of the virus' protein on their surface.
Stimulated by this display, helper T cells bind to the virus pieces on the B cells' surface. The
helper T cells secrete a chemical that tells the B cells to multiply and form clones of the
specific B cells needed to fight HIV.
4.
Some cells from the clones become memory B cells, which respond rapidly to any
encounter with the same virus.
5.
Other cells from the clones mature into plasma cells and secrete antibodies to the virus.
These antibodies bind to the virus and prevent it from infecting healthy cells.
Source: www.cnn.com
36
HOW A VACCINE WOULD HELP KILL INFECTED CELLS
Because HIV can be transmitted as a free-floating virus or through infected cells, an HIV vaccine
also would help train killer T cells to recognize immune cells infected with the virus and destroy
them.
HIV
1
2
Host Cell
3
4
KT
KT
1.
Cells Display markers on their
surface that are unique to each
individual
2.
When a virus attacks a cell,
pieces of the virus combine with
the cell’s marker and alert the
immune system that the cell is
infected
3.
The killer T cells bind to the new
marker
4.
The infected cell is destroyed by
the killer T cell, preventing the
infected cell from producing more
HIV
Source: www.cnn.com
37
8.1 VACCINE DEVELOPMENTS
Due to recent failures in the some of the latest HIV vaccination attempts researchers are now
looking in alternative directions to try and find answers to a vaccine for the HIV virus. There are
many problems in HIV control and prevention many of which stem from the HIV viruses’ ability to
replicate quite quickly and its tendency to mutate quite frequently. A single mutation in HIV is
sufficient to undermine the protection of an HIV vaccine that had apparently controlled HIV infection
in a monkey for six months. There are currently two types of vaccines that are being explored,
prophylactic and therapeutic vaccines. Prophylactic vaccines deal with prevention of the disease and
therapeutic vaccines deal with curing or treating the disease. The purpose of vaccines are to prevent
a virus from entering a healthy cell and vaccines do this by using two biologically active ingredients:
an antigen and an adjuvant. Antigens activate human immune responses while adjuvants attract
immune cells to the region where the vaccine was injected.
Although progress toward a vaccine has been a slow process in the past few years, remarkable
strides have been made toward a vaccine. In the twelve months after June 2003 thirteen vaccine
candidates had moved into Phase 1 trials. That’s the highest number of Phase 1 trials initiated in
any single year since the search for a vaccine began. A major reason for the increased number of
vaccine candidates and the progression of these candidates is the development of international
organizations in support of finding an AIDS vaccine. HIV Vaccine Trials Network (HVTN) launched
six of those Phase I trials and Bill and Melinda Gates established the Global HIV Vaccine Enterprise.
Intercontinental as well as international organizations are allowing for a plethora of information to
be spread throughout the scientific community. A huge contributor in this area is PAVE or
Partnership in AIDS Vaccine Evaluation. PAVE was established by the US government last fall and
brings together different government agencies and government funded organizations involved in
AIDS vaccine research. The new communication pipelines set up by these organizations are allowing
for better technology and quicker development. In recent years expenditures on vaccine
developments have been near $650 million with a large majority of that coming from the public
sector. Almost half this capital is allocated to preclinical research.
One reason for the slow progress in AIDS vaccines is that scientists have never before faced the
challenge of developing vaccines that work by stimulating an immune response against a disease
that actually destroys the immune system. Also, the HIV virus mutates at a very fast pace, which
outmaneuvers potential vaccines. Furthermore, different parts of the world show different strains of
AIDS, which might require different vaccines.
However, experimental HIV/AIDS vaccines have proven effective to varying degrees in stringent
animal model tests that use virus challenges that are significantly higher than what is believed to
occur in most human exposures. Individuals who become infected with HIV do not succumb to the
disease for years even in the absence of anti-retroviral therapy, suggesting that the human immune
system is capable of controlling HIV infection partially or temporarily.
To combat the different issues facing an HIV vaccination, scientists are combining different
vaccines. Many are currently in testing including: canarypox plus gp120 (Phase III); DNA plus MVA
(Phase II); recombinant adenovirus plus canarypox (Phase I); canarypox plus lipopeptides (Phase
I); and DNA plus protein (Phase I); Chiron’s (NasdaqNM: CHIR) clade B DNA+novel envelope
vaccine (Phase 1); and DNA+fowlpox clade B vaccine (Phase 1) of the University of South Wales.
Some researchers anticipate that in developing countries between the years 2005 and 2010 some
44,000 people will participate in approximately five Phase II/B and Phase III trials of AIDS vaccines
spanning fifteen countries and some 52,000 will participate in approximately ten Phase II/B and
Phase III non-vaccine HIV prevention trials, including microbicide trials spanning twelve countries.64
VACCINES IN DEVELOPMENT
DNA VACCINES
DNA vaccines are based on small rings of DNA found in bacterial cells known as bacterial plasmids.
Genes can be inserted into these rings. DNA vaccines work specifically by injecting reproduced
64
Aidsmap.com website: www.aidsmap.com
38
genetic material of the organism into the body which in turn encodes information that gets the
individuals cells to make the vaccine. The amount of DNA vaccine that it would take to produce the
desired response becomes much too large when we speak on the scale of humans as opposed to
mice. DNA vaccines are now being studied in combination with other vaccine solutions.65
DNA-based HIV Program - CytRx Corp. (NasdaqSC: CYTR)
CytRx is involved in the development of a DNA-based HIV vaccine, and has entered into strategic
alliance with UMMS (a pioneer in DNA vaccine research), and has also acquired an exclusive license
from UMMS covering a proprietary DNA-based HIV vaccine technology. The HIV vaccine technology
that they have licensed from UMMS is based upon a unique mixture of human HIV-1 primary
isolates from several genetic subtypes of HIV from primary virus isolates drawn from all over the
world. This polyvalent naked DNA (isolated, purified DNA) vaccine approach has the potential
advantages of maintaining efficacy despite the high mutation rate of HIV, a broader immune
response against divergent HIV-1 glycoproteins and the possible ability to neutralize a wide
spectrum of HIV-1 viruses. The HIV vaccine utilizes a novel "polyvalent,” which is a HIV vaccine,
based on multiple strains of HIV collected directly from infected people living in five locations around
the globe, representing five different strains of the virus. Thus, instead of hitting HIV with one
target, they are using five in this vaccine.
The goal with this vaccine is to trigger the immune system to target multiple strains of the virus.
The DNA is then boosted by an injection of recombinant viral proteins that have been shown to
enhance the host's immune response to the DNA elements of the vaccine in animal models. So far,
the DNA and protein combination has been tested in two animal models with very promising results.
Antibodies produced by the immunized animals effectively neutralized live HIV isolates collected
from several parts of the world. There is no live HIV in the vaccine, only elements from the DNA
that code for the envelope and gag proteins of the virus, so there is no chance of getting HIV from
this vaccine.
The funds under this program, totaling approximately $16 million, are expected to provide all of the
needed funding for the Phase I trial. The investigational new drug application (IND) for that trial
was filed in January 2004, and enrollment of volunteers was completed in March of 2005. The
primary objective of the Phase I clinical trial is to determine the safety and tolerability of different
dosages and routes of administration of the DNA vaccine, and a fixed dosage and route of
administration of an HIV protein boost. The vaccine strategy is to assess in human volunteers
whether a DNA vaccine with a protein boost can stimulate both antibody and T-cell immune
responses to the virus as previously demonstrated in animal models. To date, the vaccine has been
well tolerated in humans.
65
Ibid
39
DNA Vaccines
Product Name
Phase
Description
Manufacturer
HIVA
Phase
I/II
gag p17 and p24 genes plus over 25 CTL epitopes from gag, pol,
nef, env from HIV-1 subtype A in a DNA plasmid
Cobra
Pharmaceuticals
VRC4302
Phase I
gag/pol in-frame fusion expressing gag protease, RT and integrase
in a DNA plasmid
VRC-HIVDNA-009-00VP
Phase I
Multiclade HIV-1 DNA plasmid vaccine containing HIV-1 genes
gag, pol and nef from subtype B; and HIV-1 env from subtypes A,
B and C.
Vical Inc
(NasdaqNM:
VICL)
Vical Inc
(NasdaqNM:
VICL)
EP HIV-1090
Phase I
EP HIV-1090 is a DNA vaccine composed of 21 highly specific
CTL epitopes for Gag, Pol, Env, Nef, Rev and Vpr, from all of the
major subtypes and CRF. The vaccine is designed to optimize the
immune response in people expressing one of three HLA Class I
antigen subtypes: HLA-A2, -A3, and -B7. It is predicted to induce
an immune response in 85% of individuals in the general
population. In addition, PADRE, a helper T-cell epitope, is also
included. These epitopes are contained within the DNA plasmid
pMB75.6.
Epimmune
(NasdaqNM:
EPMN)
pHIS-HIV-B
Phase
I/II
modified gag gene, modified RT, rev, tat, vpu and truncated env
from HIV-1 subtype B in a DNA plasmid
Australian Thai
Vaccine
Consortium
ADVAX
Phase I
DNA vaccine containing two plasmids encoding genes from an HIV
subtype C isolate. gag and env genes are contained in one DNA
plasmid, and pol, nef and tat genes in a second plasmid.
Vical Inc
(NasdaqNM:
VICL)
Phase I
The DNA component of a DNA prime/protein boost protocol. The
vaccine contains one HIV gag gene (clade C) plus 5 HIV env
genes (one clade A, two clade B, one clade C, and one clade E).
University of
Massachusetts
Medical School
(UMMS)
Gag and Env DNA/PLG
Phase I
Clade B gag DNA/PLG and env DNA/PLG Microparticles
Chiron
(NasdaqNM:
CHIR)
VRC-HIVDNA016-00VP
Phase I
VRC-HIVDNA016-00-VP is composed of 6 closed, circular DNA
plasmids. Each of the 6 plasmids in this vaccine expresses a single
gene product. Plasmids VRC 4401, VRC 4409 and VRC 4404 are
designed to express clade B HIV-1 Gag, Pol and Nef, respectively.
VRC 5736, VRC 5737, and VRC 5738 are designed to express
HIV-1 Env glycoprotein from clade A, clade B, and clade C,
respectively. Each DNA vaccination will be administered
intramuscularly using the Biojector 2000 Needle-Free Injection
Management System.
(source: the International AIDS Vaccine Initiative (IAVI) website. IAVI is a global not-for-profit organization
working to speed the search for a vaccine to prevent HIV infection and AIDS. Founded in 1996 and operational in
23 countries, IAVI and its network of partners research and develop vaccine candidates. IAVI also advocates for a
vaccine to be a global priority and works to assure that a future vaccine will be accessible to all who need it)
RECOMBINANT VIRAL VECTORS
Adenovirus
Adenovirus is a relatively harmless and common human virus associated with cold-like illnesses.
There is a major problem associated with the adenovirus however. A large portion of the population
is naturally immune to it unfortunately in areas hit hardest with the AIDS epidemic, such as South
Africa and Thailand.
Pox Vectors
Researchers are looking at two viruses that are native to birds, fowlpox and canarypox. Pox viruses
are particularly interesting to scientist because of their ability to induce strong cytotoxic Tlymphocyte (CTL) immune responses. They are also looking at bird-adapted strains, in particular
bird strains of Vaccinia, a small pox vaccine. They are very effective as veterinary vaccines against
40
several diseases and have been engineered for humans to express multiple HIV genes. Pox include
NYVAC and modified vaccinia ankara or MVA. Canarypox had previously been used as the basis for a
commercial rabies vaccine
Replicons
In recent years, a number of research teams have created virus-like particles that contain unrelated
genetic material, called 'replicons'. These are formed by using a carrier, or 'source' virus to take the
genetic material of an unrelated virus into a cell. Replicons have the same physical properties as
viruses, including the ability to enter cells of specific kinds, but they cannot reproduce themselves.
When it comes to HIV vaccines, the three leading replicon systems are now based on alphaviruses
called Venezuelan equine encephalitis (VEE) and Semliki forest virus (SFV), and an unrelated virus
called adeno-associated virus (AAV).66
Product Name
Phase
ALVAC vCP205
Phase
I/II
MVA.HIVA
Phase
I/II
ALVAC vCP1521
Description
Manufacturer
HIV-1 subtype B envelope gp120 (MN) gene linked to the
transmembrane portion of gp41 (LAI); gag (LAI); and pol
[containing the protease portion-(LAI)], expressed in a canarypox
virus vector
gag p17 and p24, plus approximately 25 CTL epitopes (gag, pol,
nef and env) from HIV-1 subtype A, expressed in modified
vaccinia virus Ankara (MVA) vector
Sanofi-Aventis
(NYSE: SNY)
Phase III
HIV-1 subtype E envelope gp120-TM (from a primary isolate); gag
and pol [containing the protease portion) genes from HIV-1
subtype B -(LAI), expressed in a canarypox virus vector
Sanofi-Aventis
(NYSE: SNY)
ALVAC vCP1452
Phase II
All genes from HIV-1 subtype B: envelope gp120 (MN) linked to
the transmembrane portion of gp41 (LAI); pol (containing protease
sequence); gag and a synthetic polynucleotide sequence that
encodes multiple epitopes from nef and pol; two vaccinia virus
coding sequences, E3L and K3L; all of these are expressed in a
canarypox virus vector.
Sanofi-Aventis
(NYSE: SNY)
Ad5
Phase I
Codon optimized gag gene from HIV-1 subtype B expressed in a
replication defective adenovirus-5 vector
Merck
MRK)
rFPV-HIV-B
Phase
I/II
modified gag gene, modified RT, rev, tat, vpu and truncated env
from HIV-1 subtype B in a recombinant fowlpox vector
Australian
Thai
Vaccine
Consortium
AVX101
Phase I
This vaccine utilizes a propagation-defective alphavirus replicon
vector system derived from an attenuated strain of VEE virus. The
vaccine replicon expresses the gag gene from a South African
subtype C isolate of HIV-1. The vEE virus has been rendered
replication incompetent by removal of the capsid gene and the
insertion of two attenuating mutations into the gylcoprotein gene.
AlphaVax
MRKAd5 HIV-1
Phase I
Codon optimized gag gene from HIV-1 subtype B expressed in a
replication defective adenovirus-5 vector. A modifed version of the
Merck Ad5 vector
Merck (NYSE:
MRK)
VRC-HIVADV014-00VP
Phase I
VRC-HIVADV014-00-VP is a recombinant product composed of 4
adenoviral vectors (Ad) (in a 3:1:1:1 ratio) that encode the HIV-1
Gag/Pol polyprotein from clade B and HIV-1 Env glycoproteins
from clades A, B, and C, respectively. The final formulation buffer,
VRC-DILUENT013-DIL-VP will be used as the diluent and as the
placebo control. Injections will be administered intramuscularly
(IM).
GenVec
(NasdaqNM:
GNVC)
TBC-M358
Phase I
A modified vaccinia Ankara (MVA) vector containing env/gag
sequences from a clade B vertically transmitted pediatric primary
isolate.
Therion Biologics
Corporation
TBC-M335
Phase I
A modified vaccinia Ankara (MVA) vector containing modified
tat/rev/nef-RT sequences from a clade B vertically transmitted
pediatric primary isolate.
Therion Biologics
Corporation
66
Ibid
41
Impfstoffwerk
Dessau-Tornau
GmbH (IDT)
(NYSE:
Product Name
Phase
Description
Manufacturer
TBC-F357
Phase I
A fowlpox (FPV) vector containing env/gag sequences from a
clade B vertically transmitted pediatric primary isolate.
Therion Biologics
Corporation
TBC-F349
Phase I
Therion Biologics
Corporation
ADMVA
Phase I
A fowlpox (FPV) vector containing modified tat/rev/nef-RT
sequences from a clade B vertically transmitted pediatric primary
isolate.
ADMVA is a recombinant A modified vaccinia Ankara (MVA)
vector vaccine containing HIV-1 env/gag-pol and nef-tat fusion
genes based on a Chinese HIV-1 Clade C isolate
tgAAC09 AAV
Phase I
tgAAC09 is different from most other AIDS vaccine candidates
now in trials in that it is potentially a single-shot vaccine, rather
than one that would require multiple injections over time. A singleshot AIDS vaccine would be particularly useful for developing
countries, where most new HIV infections occur. tgAAC09,
containing clade C gag, pro, and rt HIV sequences, uses Targeted
Genetics’ rAAV (recombinant adeno-associated virus) and is
designed to elicit both humoral and cell-mediated responses. In
studies to date, non-human primates that received the rAAVbased vaccine showed robust and durable antibody and T-cell
responses, and also had reduced viral load when challenged with
a virulent strain of SIV, the non-human primate equivalent to HIV.
Targeted
Genetics
Corporation
(NasdaqSC:
TGEN)
Phase
IIb
MRKAd5 HIV-1 gag/pol/nef is composed of an adenovirus vector
and an HIV gene insert. The vector is adenovirus type 5 (Ad5) and
the HIV genes (gag, pol, and nef). This investigational vaccine has
been tested in more than 250 people.
Merck
MRK)
MRKAd5
gag/pol/nef
HIV-1
(source: the International AIDS Vaccine Initiative (IAVI) website)
42
Impfstoffwerk
Dessau-Tornau
GmbH (IDT)
(NYSE:
PEPTIDE VACCINES
Instead of vaccinating with a whole protein, another approach is to use a fragment of a protein,
called a peptide, which consists of a few amino acids. A vaccine containing the V3 sequences from
several strains of HIV has been used in animals and produced antibodies able to neutralize several
laboratory-adapted virus strains. Another more novel way of using a particular peptide, identified as
the target for a broadly active neutralizing antibody against HIV, is to express it on the surface of
the common cold virus. This allows the generation of a range of different varieties and the selection
of those that give the strongest immune responses. Synthetic peptides can be linked to lipid
molecules to facilitate induction of cell-mediated immune responses. Peptides can be combined as
multi-peptide vaccines as a strategy for increasing the breadth of the vaccine-induced response.67
Product Name
Phase
Description
Manufacturer
LIPO-5
Phase II
A mixture of 5 lipopeptides containing CTL epitopes from HIV-1
subtype B. Two peptides from Gag (aa 17-35; aa 253-284), two
peptides from Nef (aa 66-97; aa 116-145) and one peptide from
Pol (aa 325-355). Each peptide is modified in the C-terminal
position by the addition of a palmitoyl-lysylamide group [K(Palm)NH2 to form the lipopeptide
Sanofi-Aventis
(NYSE: SNY)
LIPO-6T
Phase I
A mixture of 5 lipopeptides containing CTL epitopes from HIV-1
subtype B and one lipopeptide containing a CD4 T-helper epitope
from TT. Two peptides from Gag (aa 183-214; aa 253-284), two
peptides from Nef (aa 66-97; aa 117-147) and one peptide from
Env (aa 303-335). In addition, a T-helper epitope from TT (aa 830846). Each peptide is modified in the C-terminal position by the
addition of a palmitoyl-lysylamide group [K(Palm)-NH2 to form the
lipopeptide.
Sanofi-Aventis
(NYSE: SNY)
LIPO-4T (LPHIV-1)
Phase I
A mixture of 4 lipopeptides containing CTL epitopes from HIV-1
subtype B (MN, LAI) proteins. One epitope from Gag (aa 77-85),
Pol-RT (aa 342-354), Pol (aa 476-484) and Nef (aa 68-82). Each
epitope contains a CD4 T-helper epitope from TT (830-843) in
colinear sequence, and at the N-terminal position a monopalmitoyl
group to form the lipopeptide.
Biovector SA
HIV CTL MEP
Phase I
The HIV CTL MEP vaccine is a mixture of four synthetic peptides,
each containing one of three different HIV CTL epitopes derived
from env or gag. The use of multiple conserved CTL epitopes will
address the extraordinary diversity found among HIV strains. The
vaccine is administered with RC529-SE, an analogue of
monophosphoryl lipid A. The vaccine/adjuvant combination will be
evaluated with or without coadministration of granulocytemacrophage colony-stimulating factor (GM-CSF).
Wyeth (NYSE:
WYE)
(source: the International AIDS Vaccine Initiative (IAVI) website)
REGULATORY PROTEINS
Several groups of researchers have been investigating the use of HIV proteins other than the
envelope proteins in vaccines. Most attention has been given to the structural (e.g. Gag) and
regulatory proteins (e.g. Tat, Nef) produced by HIV. The regulatory protein Tat is produced early
after a cell is infected with HIV, which means that cellular immune responses may destroy infected
cells before they have a chance to release more virus particles. A further advantage of this
approach is that Tat is vital to the functioning of HIV and seems to vary little between different HIV
subtypes. The Nef protein is also of interest, despite the fact that some HIV strains can infect and
cause disease without it. If cellular immune responses target cells expressing Nef, they could select
for less virulent viruses.68
67
68
Ibid
Ibid
43
Product Name
Phase
Description
Manufacturer
AIDSVAX B/E
Phase III
bivalent formulation of gp120 protein from HIV-1 subtype B (MN
isolate, a syncitium inducing strain) and subtype E (CM244
isolate, a non syncitium inducing strain) produced in CHO cells
VaxGen (OTC:
VXGN.PK)
gp160MN/LAI-2
Phase I
gp160 protein in which the gp120 SU moiety is derived from the
HIV MN strain, and the gp41 TM part from the LAI isolate
Sanofi-Aventis
(NYSE: SNY)
EnvPro
Phase I
HIV-1 gp140 protein from subtype D. This purified envelope
protein is contained in alum.
St Jude Children's
Research Hospital
Tat vaccine
EnvPro
Phase I
Phase I
Tat vaccine (HIV-1 recombinant Tat protein)
EnvPro is a Clade D purified gp140 protein in alum
Excell Biotech
St Jude Children's
Research Hospital
Phase I
The protein component of a DNA prime/protein boost protocol.
Five different recombinant gp120 proteins (one clade A, two
clade B, one clade C, and one clade E). The protein boost is
administered in combination with QS21 adjuvant.
Advanced
BioScience
Laboratories (ABL)
LFn-p24
Phase I
The WRAIR HIV vaccine, designated LFn-p24, consists of an
anthrax-derived polypeptide called Lethal factor (LFn), from
which the toxin domain has been removed, and which is fused
to the HIV-1 gag p24 protein. The vaccine is aimed at inducing
strong and persistent HIV-1 gag specific CD8 T Cell responses.
AVANT
Immunotherapeutics,
Inc. (NasdaqNM:
AVAN)
Recombinant,
Oligomeric
gp140/MF59 Adjuvant
Phase I
Clade B Recombinant, Oligomeric gp140/MF59 Adjuvant
Chiron (NasdaqNM:
CHIR)
AS02A
Phase I
clade B Nef-Tat fusion protein + clade B Env subunit
GlaxoSmithKline
(NYSE: GSK)
(source: the International AIDS Vaccine Initiative (IAVI) website)
BACTERIAL DELIVERY OF DNA
As DNA vaccines are grown inside bacteria, it may be possible to use the bacteria themselves as the
vaccine. Immune responses can be induced to DNA plasmids included in weakened vaccine strains
of such bacteria as Salmonella and Shigella, which usually infect humans via the oral route and
induce strong mucosal immune responses If this strategy succeeds, it opens the way to an oral
vaccine.
Product Name
GTU-MultiHIV B clade
Phase
Phase
I/II
Description
GTU®MultiHIV B clade, DNA based vaccine containing a naked
DNA plasmid. Antigens: nef, rev, tat, gag, pol, env, CTL epitopes.
Manufacturer
FIT Biotech
(source: the International AIDS Vaccine Initiative (IAVI) website)
OTHER VECTORS
Of the other viral vectors being studied with HIV, measles is of particular interest. The live
attenuated measles vaccine in common use is extremely effective in generating long-lasting
immune responses when given to infants, which can be boosted in adolescents. This might be ideal
to protect young people in countries where HIV is widespread.
NEW FRONTIERS
Recently, a novel system to develop and screen for potential vaccines has been developed. The
process is known as “Molecular Breeding” and was developed by Maxygen Inc. (NasdaqNM:
MAXY). The process consists of placing chopped up viral sequences in a test tube. The gene
fragments then express their corresponding proteins. This enables researchers to select the proteins
with desired properties, such as the ability to bind strongly to a particular HIV antibody. The
selected sequences are then used to start the whole process over again. In time this can produce
virus gene sequences that illicit an even stronger immune response.
44
VACCINE-LIKE TREATMENTS
PEHRG214 – Virionyx
Scientists are also attempting to stimulate the immune system using a genetically engineered group
of antibodies to HIV similar to a vaccine. It will be administered to patients who currently are
infected with the HIV virus. PEHRG214 uses antibodies from immunized goat plasma to target
portions of the HIV virus that are not recognized by the human immune system but are readily
recognized by goat immune systems. PEHRG214 may also be referred to as a “passive immunotherapeutic pharmaceutical” and is currently in a Phase II trial.69
DermaVir® - Research Institute for Genetic & Human Therapy (RIGHT)
DermaVir® is a novel therapeutic vaccine that is applied to the skin. It is the least invasive of
antiviral treatment and can be administered as little as 8 times a year. It is in Phase I trials. The
infrequent dosing, high viral suppression and low toxicity profile make DermaVir® very appealing to
patients. It also appears to prevent viral rebound. DermaVir® will most likely be used along with
standard HAART treatments.70
VIR201- Virax Holdings Limited (ASX: VHL)
VIR201, in Phase I/IIa trials, uses DNA vaccine technology called Co-X-Gene. This vaccine carries a
fake virus onto which HIV and human genetic material have been grafted. The vaccine stimulates
the HIV-specific immune response to fight the HIV virus. This vaccine will be helpful in people with
low levels of HIV in their blood because it will help them to continue fighting the virus even when
the body would normally stop.71
69
Virionyx Corporation Ltd. Company website. For more information please visit: www.virionyx.com
Hivandhepatitis.com is online publication with the goal of providing accurate, timely and cutting-edge information about
treatment for HIV/AIDS, chronic hepatitis B and hepatitis C, and co-infection with HIV/HCV and HIV/HBV. Please visit:
www.hivandhepatitis.com for more information.
71
Virax Holdings Limited company website. For more information please visit: www.virax.com.au
70
45
9.
CONCLUSION
The world is aware of the rising threat of AIDS. Last year alone almost five million additional people
around the world became infected with HIV and three million people died from AIDS. With the
present treatments available patients are able to live longer but the mortality rate for HIV infection
is approaching 100 percent. Currently more developed nations are reaching out to areas of the
world that are plagued by this epidemic, in particular areas of sub-Saharan Africa. With a growing
epidemic occurring in China the need to put an end to this disease has never been more important.
In the United States there were approximately 900,000 people living with HIV infection; however,
nearly one-quarter of these HIV infected individuals did not know they were infected. This year
alone 40,000 more people will become infected with an ever growing number of women and
minorities becoming newly infected. AIDS deaths in the United States have fallen, but this may be
attributable to the use of antiretroviral drugs which only allow patients to live longer without curing
the disease. While the current therapies such as protease inhibitors and reverse transcriptase
inhibitors have helped many patients with AIDS to manage their disease, these therapies are not
curative and often have significant side-effects which can often be treatment limiting. Compliance
with a regimen is a very serious issue when dealing with the treatment of HIV, and many times
HAART will fail because of a patient’s inability to comply with the dosing regimen. Limiting the
dosing regimen and reducing side effects are two major obstacles that drug companies must face
when developing drugs. If too many doses are missed the virus may develop a resistance to a
certain drug in turn causing cross-resistance with all other drugs in a given class. If resistance or
any kind of mutation occurs the HIV virus can be very difficult to control. The latest unfavorable
news is that doctors believe they may have found an unusually virulent strain of HIV that is
resistant to most antiretroviral drugs. It is able to progress to symptomatic AIDS within as little as
four months. With new challenges facing doctors the need to pursue next generation therapies to
serve unmet needs is hastening.
HIV is notorious for its ability to change, or mutate, and thereby evade the effects of drugs. HIV
infection is characterized by high rates of viral replication, eventually leading to depletion of CD4
cells and disease progression. A high frequency of replication results in a high frequency of viral
mutations, resulting in many different strains of virus, each with slightly different genes. The
mutation rate in HIV is also very high because the enzyme responsible for copying the viral genetic
code is inefficient and makes numerous mistakes. It has been calculated that every possible single
point HIV mutation may occur more than 10,000 times a day in an infected person. The
development of drug resistance is the most common cause of treatment failure.
The potential for large revenues as well as the HIV market’s rapid growth have made it very
attractive to large pharmaceutical companies such as GlaxoSmithKline, Gilead, Bristol-Myers
Squibb, Merck & Co., Roche, Pfizer, Abbott Laboratories and Boehringer Ingelheim. Expansion of
screening programs and the increase in the diagnosis rate for HIV is expected to further bolster the
patient population available for treatment and thus drive the value of the market. Growth in the
global HIV market is expected to create opportunities to expand sales for drug companies currently
in the market while still opening opportunities for more novel drugs from other drug companies. To
battle the development of growing resistance and declining immune responses, the addition of more
entry inhibitors and immune based adjunct therapies will influence the current market share of
many companies.
Currently there are 25 AIDS drugs approved by the FDA. They include Nucleoside Reverse
Transcriptase Inhibitors (NRTIs), Protease Inhibitors (PIs), Non-Nucleoside Reverse Transcriptase
Inhibitors (NNRTIs); and Fusion Inhibitors. These drugs are usually used in combinations of three or
more to create an effective antiviral therapy. In addition, there are multiple investigational new
drug applications (INDs) that have been submitted to the U.S. Food and Drug Administration to
conduct clinical trials on anti-HIV candidates. None of the currently approved drugs kill the HIV
virus, but each class slows down the replication of the virus in a particular way.
GlaxoSmithKline (NYSE: GSK) continues to be the strongest franchise in NRTIs. The easy dosing
regimen provided by drugs such as Combivir® allows the drug giant to hold the top spot. Gilead
Sciences (NasdaqNM: GILD) now holds the number two spot in the NRTI market largely due to
the success of Viread® which has been shown to be very effective in salvage therapy.
46
Nucleoside Analogue Reverse Transcriptase Inhibitors (NRTIs or Nukes) form the backbone of every
HIV HAART treatment regimen, with two drugs from this class generally included in every patient’s
drug combinations. NRTIs block reverse transcription (the creation of viral DNA from RNA) by
providing “decoy” building blocks that interrupt the process. There are currently 12 FDA approved
Nucleoside Analogues. They are as follows:
•
•
•
•
•
•
•
•
•
•
•
•
Zidovudine; AZT; Azidothymidine; Retrovir® (GlaxoSmithKline, NYSE: GSK);
Didanosine; Dideoxyinosine; ddI; Videx® (Bristol-Myers Squibb, NYSE: BMY);
Zalcitabine; Dideoxycytidine; ddC; Hivid® (Roche, OTC: RHHBY.PK);
Lamivudine; 3TC; Epivir® (GlaxoSmithKline, NYSE: GSK);
Stavudine; D4T; Zerit® (Bristol-Myers Squibb, NYSE: BMY);
Abacavir Succinate; 1592U89 Succinate; Ziagen® (GlaxoSmithKline, NYSE: GSK);
Combivir®; lamivudine & zidovudine; 3TC & AZT (GlaxoSmithKline, NYSE: GSK);
Trizivir®; abacavir & lamivudine & zidovudine; (GlaxoSmithKline, NYSE: GSK);
Tenofovir; PMPA; Viread® (Gilead, NasdaqNM: GILD);
Emtricitabine; FTC; Emtriva® (Gilead, NasdaqNM: GILD);
Emticitabine and tenofovir; Truvada® (Gilead, NasdaqNM: GILD); and
Abacavir and lamivudine; Epzicom® (GlaxoSmithKline, NYSE: GSK).
Bristol-Myers Squibb’s (NYSE: BMY) Sustiva® continues to be the market leader in NNRTIs.
Sustiva® has managed 13.8% share of the new prescriptions in the NNRTI and NRTI market
combined. Sustiva® also continues to be the most prescribed product among PIs and NNRTIs.
Sustiva® has 65 percent of the new and total NNRTI prescriptions. Sustiva®’s success is most
likely to due to its low pill burden and once-daily dosing. NNRTIs and PIs must compete against
one another for the third part of the triple drug cocktail thus making advances in either arena able
to drastically affect the market.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs or non-nukes) are the newest class of
anti-virals that have made a major impact on the global HIV market. NNRTIs interrupt reverse
transcription, by binding to the reverse transcriptase enzyme and restricting its activity. There are
currently 3 FDA Approved Non-Nucleoside Reverse Transcriptase Inhibitors. They are as follows:
•
•
•
Nevirapine; BI-RG-587; Viramune® (Boehringer Ingelheim);
Delavirdine; BHAP; U-90152; Rescriptor® (Pfizer (Agouron Unit), NYSE: PFE); and
Efavirenz; DMP-266; Sustiva® (Bristol-Myers Squibb, NYSE: BMY).
Abbott Pharmaceutical’s (NYSE: ABT) Kaletra® is currently the leader among protease
inhibitors. Kaletra®’s favorable testing results, when compared to other antiviral drugs, have
propelled it to the top of the PI market. Its ability to suppress viral loads exceeded that of
Viracept®. In long term studies Kaletra® has shown amazing durability as well. Kaletra® was
recently the leader in new PI subscription and total PI subscriptions. However, Kaletra® is losing
ground to some of the newer protease inhibitors on the market including Bristol-Myers Squibb’s
(NYSE:
BMY)
Reyataz®
which
appears
to
be
safe
and
very
potent
and
GlaxoSmithKline/Vertex’s (NYSE: GSK, NasdaqNM: VRTX) Lexiva® which has a low pill
burden and flexibility in dosing not offered by other PIs.
Protease Inhibitors (PIs) are considered an extremely powerful class of anti-viral drugs, blocking
the action of protease, an enzyme that cuts HIV protein chains into specific proteins needed to
assemble a new copy of the virus. The high dosage levels associated with PIs however, are a
negative factor, as is their relatively poor side effect profile. There are currently 9 FDA approved
Protease Inhibitors. They are as follows:
•
•
•
•
•
•
•
•
Saquinavir; Ro 31-8959; Fortovase®; Invirase® (Roche, OTC: RHHBY.PK);
Indinavir; MK639; L-735, 524; Crixivan® (Merck, NYSE: MRK);
Ritonavir; ABT-538; Norvir® (Abbott Laboratories, NYSE: ABT);
Nelfinavir; AG-1343; Viracept® (Pfizer / Agouron unit, NYSE: PFE);
Amprenavir; VX-478; 141W94; Agenerase® (GlaxoSmithKline, NYSE: GSK);
Kaletra®; lopinavir & ritonavir; ABT-378r (Abbott Laboratories, NYSE: ABT);
Atazanavir; BMS-232632; Reyataz® (Bristol-Myers Squibb, NYSE: BMY); and
Fosamprenavir; GW433908; Lexiva® (GlaxoSmithKline, NYSE: GSK).
47
Roche Pharmaceuticals (OTC: RHHBY.PK) and Trimeris, Inc. (Nasdaq: TRMS) are the
leaders in the HIV fusion inhibitor category with their leading product Fuzeon®. Fuzeon® has faced
its difficulties because doctors have been reluctant to prescribe Fuzeon® because of their apparent
concern about patient compliance. The rate of new prescriptions for Fuzeon® dropped
approximately 50 percent in 2004, yet Fuzeon® was able to achieve worldwide sales of $135 million
in 2004 (+27%) despite the reluctances of doctors. There are currently multiple entry or
attachment inhibitors in the drug pipeline that are progressing rapidly.
Fusion Inhibitors attempt to inhibit viral attachment and thus prevent HIV from entering the human
cell. Scientists hope that by targeting particular sites on both the human cell and the HIV virus that
serve as receptors when the virus attaches to the human cell they will be able to prevent infection.
One of these receptors is known as the CCR5 receptor. The CCR5 receptor helps direct immune cells
to damaged or diseased areas of the body. This is how HIV enters and infects T cells. There is
currently only one FDA approved fusion inhibitor:
•
Enfuvirtide; T-20; Fuzeon® (Roche Pharmaceuticals, OTC: RHHBY.PK) and (Trimeris,
Inc., Nasdaq: TRMS)
Immune-based therapy will most likely play a major role in fighting HIV in the future. The immune
modulators are designed to help the efforts of one or more of the “arms” of the immune system:
antibodies; natural killer cells; killer T cells; and helper T cells. In addition, the immune modulators
may also prove effective at flushing out latent virus that may remain hidden in many cells and
lymphoid tissues of the body (and virtually undetected in the blood). This reservoir of latent cells is
believed to be one of the major barriers to completely eliminating HIV from a person’s body.
Companies that are currently pursuing various immune therapy strategies include many wellknown drug companies including Chiron Corporation (NASDAQ: CHIR); Bayer Corporation
(NYSE: BAY); and GlaxoSmithKline (NYSE: GSK).
The goal of developing an HIV vaccine is an area of great interest to scientists and drug
manufacturers alike. Although progress toward a vaccine has been a slow process with numerous
failures in the clinc, in the past few years remarkable strides have been made toward a vaccine for
HIV. In the twelve months after June 2003 thirteen vaccine candidates moved into Phase I trials.
That’s the highest number of Phase I trials initiated in any single year since the search for a
vaccine began. A major reason for the increased number of vaccine candidates and the progression
of these candidates is the development of international organizations in support of finding an AIDS
vaccine. Many vaccines are currently being tested utilizing recombinant viral vectors, DNA vaccines
and combinations of peptides and lipids to deliver the vaccine. Some researchers anticipate that in
developing countries between the years 2005 and 2010 some 44,000 people will participate in
approximately five Phase II/B and Phase III trials of AIDS vaccines spanning fifteen countries and
some 52,000 will participate in approximately ten Phase II/B and Phase III Non-vaccine HIV
prevention trials, including microbicide trials spanning twelve countries. Sanofi-Aventis (NYSE:
SNY); Merck & Co. (NYSE:MRK); as well as Chiron Corporation (NasdaqNM: CHIR) all have
multiple vaccines in development.
48
DISCLOSURES
ANALYST(s) CERTIFICATION: The analyst(s) responsible for covering the securities in this report certify that the views expressed
in this research report accurately reflect their personal views about the Company and its securities. The analyst(s) responsible for
covering the securities in this report certify that no part of their compensation was, is, or will be directly or indirectly related to the
specific recommendation or view contained in this research report.
RATINGS: Griffin Securities, Inc. currently has a BUY rating on the shares of CytRx Corp. (NasdaqSC: CYTR) and Hemispherx
Biopharma, Inc. (AMEX: HEB). Griffin Securities, Inc. has no investment ratings on any of the other companies mentioned in this
report, which include: GlaxoSmithKline (NYSE: GSK), Gilead Sciences (NasdaqNM: GILD), Abbott Pharmaceuticals (NYSE: ABT),
Vertex Pharmaceuticals (NasdaqNM: VRTX), Bristol-Meyers Squibb (NYSE: BMY), Pfizer (NYSE: PFE), Roche Pharmaceuticals
(OTC: RHHBY), Trimeris (NasdaqNM: TRMS), Chiron Corp (NasdaqNM: CHIR), Merck (NYSE: MRK), Aethlon Medical (OTCBB:
AEMD), Sanofi-Aventis (NYSE: SNY), VaxGen (OTC: VXGN), Medivir (Stockholm: MVIRb.ST), Achillion Pharmaceuticals (privately
held), Pharmasset (privately held), Incyte Corporation (NasdaqNM: INCY), Avexa Ltd. (ASX: AVX.AX), Boehringer Ingelheim
(privately held), Johnson & Johnson (NYSE: JNJ), Koronis Pharmaceuticals (privately held), Procyon Biopharma (Toronto: PBP.TO),
AnorMed (Toronto: AOM.TO), Ono Pharmaceutical (OTC: OPHLF.PK), Progenics (NasdaqNM: PGNX), Schering Plough (NYSE:
SGP), Tanox (NasdaqNM: TNOX), Biogen Idec (NasdaqNM: BIIB), Samaritan Pharmaceuticals (AMEX: LIV), Bayer Corporation
(NYSE: BAY), Cel-Sci Corporation (AMEX: CVM), Amgen (NasdaqNM: AMGN), Regeneron Pharmaceuticals (NasdaqNM: REGN),
Hollis-Eden Pharmaceuticals (NasdaqNM: HEPH), Medarex (NasdaqNM: MEDX), VI Technologies (NasdaqNM: VITX), H-Phar
Pharmaceuticals (privately held), Enzo Biochem (NYSE: ENZ), VIRxSYS (privately held), Vical (NasdaqNM: VICL), Epimmune
(NasdaqNM: EPMN), Cobra Pharmaceuticals (privately held), GenVec (NasdaqNM: GNVC), Therion Biologics Corporation (privately
held), Targeted Genetics Corporation (NasdaqSC: TGEN), Wyeth (NYSE: WYE), AVANT Immunotherapeutics (NasdaqNM: AVAN),
Advanced BioScience Laboratories (privately held), Excell Biotech (privately held), FIT Biotech (privately held), Virax Holdings
Limited (ASX: VHL), and Maxygen (NasdaqNM: MAXY),
MEANINGS OF RATINGS: Our rating system is based upon 12 to 36 month price targets. BUY describes stocks that we expect to
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expect to decline by more than 20%. SC describes stocks that Griffin Securities has Suspended Coverage of this Company and
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previous investment rating and price target, if any, are no longer in effect for this stock and should not be relied upon. NR
describes stocks that are Not Rated, indicating that Griffin Securities, Inc. does not cover or rate this Company.
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overall profitability of Griffin Securities, including profits derived from investment banking revenue. The analyst(s) that prepared the
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currently own securities in Hemispherx Biopharma or CytRx Corp., but in the future may from time to time engage in transactions
with respect to the Company or other companies mentioned in the report. Griffin Securities, Inc. from time to time in the future may
request expenses to be paid for copying, printing, mailing and distribution of the report by the companies mentioned in this report or
compensation for products and other than investment banking. Griffin Securities has received no compensation for investment
banking services from the companies mentioned in this report. Griffin Securities or an affiliate may seek to perform investment
banking services for any of the companies mentioned in this report in the future and would intend to seek compensation for any
such services.
DISTRIBUTION OF RATINGS:
Currently Griffin Securities, Inc. has assigned BUY ratings or NOT RATED (NR) on all of the companies it covers. The Company
has not provided investment-banking services for any of the companies in these categories.
DISCLOSURES FOR OTHER COMPANIES MENTIONED IN THIS REPORT:
To obtain applicable current disclosures in electronic format for the subject companies in this report, please refer to SEC Edgar
filings at www.SEC.gov on the Internet. In particular, for a description of risks and uncertainties related to subject companies’
businesses in this report, see the “Risk Factors” section in the SEC filings.
GENERAL:
Griffin Securities, Inc. a NASD member firm with principal offices located in New York, New York, USA is a full-service, integrated
investment banking, investment management, and brokerage firm. The analyst(s) are employed by Griffin Securities, Inc., Our
research professionals provide important input into our investment banking and other business selection processes. Our
salespeople, traders, and other professionals may provide oral or written market commentary or trading strategies to our clients that
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reflect opinions that are contrary to the opinions expressed herein, and our proprietary trading and investing businesses may make
investment decisions that are inconsistent with the recommendations expressed herein.
In reviewing these materials, one should be aware that any or all of the disclosures, among other things may give rise to real or
potential conflicts of interest. The information contained herein is not a complete analysis of every material fact respecting any
company, industry or security. This material should not be construed as an offer to sell or the solicitation of an offer to buy any
security in any jurisdiction where such an offer or solicitation would be illegal. We are not soliciting any action based on this material.
It is for the general information of clients of Griffin Securities, Inc. It does not take into account the particular investment objectives,
financial situations, or needs of individual clients. Before acting on any advice or recommendation in this material, clients should
consider whether it is suitable for their particular circumstances and, if necessary, seek professional advice. Certain transactions including those involving futures, options, and other derivatives as well as non-investment-grade securities - give rise to substantial
risk and are not suitable for all investors. The material is based on information that we consider reliable, but we do not represent that
it is accurate or complete, and it should not be relied on as such. The information contained in this report is subject to change
without notice and Griffin assumes no responsibility to update the report. In addition, regulatory, compliance, or other reasons may
prevent us from providing updates.
This Report contains forward-looking statements, which involve risks and uncertainties. Actual results may differ significantly from
such forward-looking statements. Factors that might cause such a difference include, but are not limited to, those discussed in the
“Risk Factors” section in the SEC filings available in electronic format through SEC Edgar filings at www.SEC.gov on the Internet.
Griffin Securities, Inc. from time to time perform corporate finance or other services for some companies described herein and may
occasionally possess material, nonpublic information regarding such companies. This information is not used in preparation of the
opinions and estimates herein. While the information contained in this Report and the opinions contained herein are based on
sources believed to be reliable, Griffin Securities, Inc. has not independently verified the facts, assumptions and estimates contained
in this Report. Accordingly, no representation or warranty, express or implied, is made as to, and no reliance should be placed on,
the fairness, accuracy, completeness or correctness of the information and opinions contained in this Report.
Griffin and/or its affiliates, shareholders, officers, directors, and employees, including persons involved in the preparation or
issuance of this material, and/or members of their family may from time to time have "long" or "short" positions in, act as principal in,
act as a block positioner and buy or sell the securities or derivatives (including options) or perform other transaction(s) with respect
to the companies mentioned herein. In addition, Griffin Securities, Inc. or its affiliates may from time to time perform investment
banking or other services for, or solicit investment banking or other business from, any entity mentioned in this report.
This material has been issued by Griffin Securities, Inc. and has been approved by Griffin Securities, Ltd. in connection with its
distribution in the United Kingdom. Foreign-currency-denominated securities are subject to fluctuations in exchange rates that could
have an adverse effect on the value or price of, or income derived from, the investment. In addition, investors in securities such as
ADRs, the values of which are influenced by foreign currencies, effectively assume currency risk. In addition, options involve risk
and are not suitable for all investors.
The information herein was obtained from various sources; we do not guarantee its accuracy or completeness. ADDITIONAL
INFORMATION AVAILABLE UPON REQUEST. No part of this material may be (i) copied, photocopied, or duplicated in any form
by any means or (ii) redistributed without Griffin Securities, Inc.'s prior written consent.
© Griffin Securities, Inc., 2005. All rights reserved.
Griffin Group plc is listed on the London Stock Exchange, Alternative Investment Market, under the symbol:
“GFF” and as an ADR sponsored by The Bank of New York under the symbol “GGPFY”.
Griffin's New York offices:
Griffin Securities, Inc.
17 State Street, NY, NY 10004
Tel: 212-509-9500
Email: [email protected]
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