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FUZEON (T-20) Approved by the FDA
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The availability of this new drug T-20 is an important milestone for patients
with resistance to the currently available drugs for HIV: protease
inhibitors, NNRTIs, and nukes. T-20 is the first new drug in a new class of
anti HIV drugs, entry inhibitors. T-20 is a fusion inhibitor which is a type
of entry inhibitors. The availability of T-20 means that patients with
resistance to the currently available classes of drugs should be sensitive to
this new class of drugs and will have a new and effective treatment option.
This should help many patients stay healthy by keeping HIV viral load at bay
and increasing CD4 counts. The phase III studies that showed the benefits of
T-20 in treatment experienced patients are the TORO I and TORO II studies.
The FDA approved T-20 "in combination with other antiretroviral agents is
indicated for the treatment of HIV-1 infection in treatment-experienced
patients with evidence of HIV-1 replication despite ongoing antiretroviral
therapy", meaning resistance to current classes of HIV drugs. T-20 is
administered by a subcutaneous injection, like insulin, twice daily. The side
effects and safety profiles are reported below. The main side effect is
injection site reactions that occur at the site of injecting T-20, most
patients experienced these in the studies. Other than the injection site
reactions T-20 appears to show no other serious side effects in high
incidence in the TORO I and II studies. Researchers are in early stages of
looking for new and various types of entry inhibitors that work at different
points in the process of HIV's entry into the CD4 cell, where HIV uses the
CD4 cell for reproducing itself. T-20 is a difficult drug to manufacture as
it is the first drug of it's type to indeed be manufactured for commercial
use. This point was explained by Trimeris, the company who originally
developed T-20, a few years ago when the drug was in the early stages of
development. Therefore, there are supply concerns. T-20 is expected to be in
the pharmacy by the end of March but there is expected to be a limited supply
which may or may not be adequate for immediate demand. Roche is ramping up
production this year so supply will increase throughout this year and next as
manufacturing capacity and procedures improve.
The FDA approved T-20 yesterday March 13 at the end of the business day. This
report contains immediately below several links to NATAP Reports on T-20
which contain the most up to date results from studies, safety data, and how
to optimize T-20 use. Following these links are the FDA Approval Press
Release, the Roche Press Release, and a report in the current New England
Journal of Medicine summarizing the TORO I results.
NATAP Reports on T-20:
Results From the Two T-20 Large Phase III Studies, TORO I and TORO II,
reported at the Intl AIDS Conference in Barcelona
http://www.natap.org/2002/barcelona/day1.htm
T-20 Safety Reported at Retrovirus 2003 in Report on Entry Inhibitors,
including Report on T-1249, 2nd generation fusion inhibitor in T-20
experienced patients:
http://www.natap.org/2003/Retro/day34.htm
T-20 and T-1249: report from ICAAC Conference on how co-factors in success
using T-20
http://www.natap.org/2002/ICAAC/day10.htm
FDA Press Release on Fuzeon
"First drug in a new class of HIV/AIDS treatments for HIV-infected adults and
children with advanced HIV infection"
The Food and Drug Administration (FDA) approved FUZEON (enfuvirtide, also
known as T-20) on Thursday, March 15, 2003, for use in combination with
other anti-HIV medications to treat advanced HIV-1 infection in adults and
children ages 6 years and older.
FDA's approval of FUZEON is the first, worldwide, of a new class of drugs
known as "fusion inhibitors." Fusion inhibitors interfere with the entry of
HIV-1 into cells by inhibiting the merging of the virus with the cellular
membrane, the first step in viral infiltration. This inhibition blocks HIV
before it enters the human immune cell.
Combination therapy using multiple medications is used to effectively treat
HIV infection. However, a significant percentage of patients with chronic
HIV have developed infection resistant to many existing medications.
Because of its unique mode of action, FUZEON may be active against HIV that
is resistant to currently available classes of anti-HIV drugs.
FUZEON, administered twice daily as a subcutaneous injection (under the
skin), can be used as part of a treatment regimen in patients for whom there
are limited options. It should only be used in patients who have used other
anti-HIV medications and show evidence of ongoing viral replication.
FDA based its approval on an analysis of six months of data from two ongoing
clinical studies of FUZEON involving approximately 1,000 patients. The data
from this analysis showed that the addition of FUZEON to a combination of
other antiretroviral medications reduced viral load in the blood, a measure
of HIV infection, more than the use of the combination of medications alone.
FUZEON was studied in 35 pediatric patients from the age of 6 years to 16
with pharmacokinetic data from 18 of these patients.
The long-term effects of FUZEON are not known at this time, but are being
evaluated by ongoing clinical studies.
The approved labeling for FUZEON warns physicians to carefully monitor
patients for signs and symptoms of pneumonia. Although bacterial pneumonia
was not common in clinical study participants, more patients treated with
FUZEON developed bacterial pneumonia than did patients who did not receive
FUZEON. Patients receiving FUZEON are advised to seek medical evaluation
immediately if they develop signs or symptoms suggestive of pneumonia, such
as cough with fever, rapid breathing and shortness of breath.
In addition, FUZEON can cause serious allergic reactions, and local skin
reactions at the site of injection.
Symptoms of a serious allergic reaction with FUZEON can include: trouble
breathing, fever with vomiting and a skin rash, blood in urine, and swelling
of the feet. Patients taking FUZEON should contact their healthcare provider
right away if they experience any of these symptoms.
Local skin reactions from FUZEON injections are common, occurring in almost
all patients, and may be painful. Patients must be careful that their skin
does not become infected at the site of injection. It is important to follow
the injection Instructions that come with the medication to lower the
chances of getting an injection site infection.
Patients should call their health care provider if there are signs of
infection at the injection site such as drainage, increasing heat, swelling,
redness or pain.
Because of the molecular complexity, and difficulty of manufacture, it is
possible that demand for FUZEON may exceed supply at launch. The sponsor is
working with HIV physician and patient groups to develop a progressive
launch plan, and will carefully manage allocation of FUZEON.
Roche Pharmaceuticals of Nutley, N.J., has licensed the product from
Trimeris Inc. of Durham, N.C., and will distribute FUZEON.
Roche Press Release on Fuzeon approval by FDA
"U.S. FDA Approves FUZEON'; First Drug to Block Entry of HIV into Immune
Cells"
FUZEON leads first new class of anti-HIV drugs since 1996
NUTLEY, N.J., and DURHAM, N.C. (March 13, 2003) - Roche and Trimeris, Inc.
(Nasdaq: TRMS) announced today that FUZEON (enfuvirtide), a novel treatment
for HIV-1, has been granted accelerated approval by the U.S. Food and Drug
Administration (FDA) following a six-month priority review. FUZEON in
combination with other antiretroviral agents is indicated for the treatment
of HIV-1 infection in treatment-experienced patients with evidence of HIV-1
replication despite ongoing antiretroviral therapy.
FUZEON is the first fusion inhibitor, representing the first new class of
anti-HIV treatments in seven years. Unlike all currently approved anti-HIV
drugs, FUZEON blocks the virus from entering the human immune cell,
preventing HIV replication that can devastate the immune systems of HIV
infected individuals.
"This new fusion inhibitor is a significant breakthrough and its approval is
a milestone event in the HIV epidemic," said Dr. Michael Saag, Director, AIDS
Outpatient Clinic, University of Alabama at Birmingham. "Patients are
becoming resistant to our best therapies and they need new options. This
drug attacks the virus in a new way, so it can work for patients whose virus
is resistant to other therapies."
"Almost one million people in the United States are living with HIV/AIDS, and
over 28,000 of those people are living here in New Jersey. Today, thanks to
Roche, whose U.S. headquarters is located right here in Nutley, New Jersey,
there is new hope for these patients. Today, the FDA approved FUZEON, the
first in a new-class of HIV drugs called fusion inhibitors. I am extremely
proud that Roche, and its 3,000 employees who live and work in New Jersey,
together with their partner Trimeris Inc., are responsible for this
incredible breakthrough in the treatment for HIV/AIDS," said Rep. Bill
Pascrell (D-New Jersey). "New Jersey's AIDS Drug Assistance Program helps
provide these life-sustaining HIV treatments to approximately 3,400 uninsured
and underinsured individuals. In Congress, I've worked and will continue to
work towards greater funding for this important program."
Pivotal Data
The regulatory submission for FUZEON was based on data from two 24-week Phase
III pivotal studies of approximately 1,000 patients, TORO (T-20/FUZEON vs. O
ptimized Regimen Only) 1, conducted in North America and Brazil, and TORO 2,
conducted in Europe and Australia. These studies showed that
treatment-experienced patients receiving FUZEON as a part of an optimized
background regimen (individualized combination of anti-HIV drugs) experienced
greater immunologic improvements and were twice as likely to achieve
undetectable plasma levels of HIV (HIV-1 RNA of <400 copies/mL) compared to
patients receiving an individualized regimen alone. In addition, those
patients with two or more active drugs in their background regimen were more
likely to achieve undetectable levels of HIV.
Because of the public health implications, The New England Journal of Medicine
(NEJM) will post the clinical results from the FUZEON TORO 1 study on its
web site, www.nejm.org in advance of publishing the data in an upcoming
issue. (edit note from Jules Levin:You can read this NEJM report at the end
of this press release, where I've inserted the report).
"With FUZEON, what we've essentially done is to take a piece of the virus and
turn it against itself. The safety and efficacy of this new molecule were
demonstrated through two rigorously-designed pivotal studies conducted in a
diverse treatment-experienced patient population," said Dr. Dani Bolognesi,
Chief Executive Officer, Trimeris. "Together with our partner Roche,
Trimeris is proud to bring this innovative new therapy to the growing number
of people with HIV who are in need of new treatment options."
"FUZEON is yet another example of Roche's long-standing commitment to
advancing the treatment of HIV," said George B. Abercrombie, President and
Chief Executive Officer, North American Pharmaceuticals Operations, Roche.
"FUZEON also represents a major advancement in the large-scale chemical
synthesis of peptides. This cutting edge process has been successfully
implemented at the Roche manufacturing facility in Boulder, Colorado. FUZEON
adds an important dimension to our growing HIV product portfolio and opens
the door for a new treatment paradigm in HIV."
Supply and Distribution of FUZEON
Roche and Trimeris have committed to make FUZEON available for distribution
before the end of March. Because initial demand for FUZEON may exceed supply
following commercial availability, Roche and Trimeris have developed and are
now finalizing a US Progressive Distribution Plan to provide FUZEON to
patients and to ensure uninterrupted supply to patients once they begin
therapy. The details of this US Progressive Distribution Plan will be
announced in the near future.
Approved Indication
FUZEON in combination with other antiretroviral agents is indicated for the
treatment of HIV-1 infection in treatment-experienced patients with evidence
of HIV-1 replication despite ongoing antiretroviral therapy. This indication
is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in
controlled studies of FUZEON of 24 weeks' duration. Subjects enrolled were
treatment-experienced adults; many had advanced disease. There are no
studies of FUZEON in antiretroviral naive patients. There are no results
from controlled trials evaluating the effect of FUZEON on clinical
progression of HIV-1.
This indication is reflective of a policy shift within the anti-viral
division at FDA designed to ensure that indications more closely reflect the
patient populations studied.
More About FUZEON
FUZEON is administered as a twice-daily subcutaneous injection. Local
injection site reactions were the most frequent adverse events associated
with the use of FUZEON. In Phase III clinical studies, 98 percent of
patients had at least one local injection site reaction. The addition of
FUZEON to background antiretroviral therapy generally did not increase the
frequency or the severity of the majority of adverse events. There was less
than five percent difference in the most common adverse events seen between
FUZEON plus an individualized regimen of antiretroviral drugs and
individualized regimen alone. The events most frequently reported in
subjects receiving FUZEON plus an individualized regimen were diarrhea
(26.8%), nausea (20.1%), and fatigue (16.1%). All these events were seen at
a lower incidence than in subjects that received background regimen alone:
diarrhea (33.5%), nausea (23.7%), and fatigue (17.4%). The most common
adverse events seen more frequently in patients receiving FUZEON plus an ind
ividualized regimen than in patients who received treatment without FUZEON
include headache (11.8%), peripheral neuropathy (8.9%), dizziness (6.6%),
insomnia (11.3%), depression (8.6%), decreased appetite (6.3%), asthenia
(5.7%), myalgia 5.0%), constipation (3.9%) and pancreatitis (2.4%). The
majority of adverse events were of mild or moderate intensity.
Hypersensitivity reactions have been associated with FUZEON therapy (²1
percent) and have recurred on rechallenge. In addition, an increased rate of
bacterial pneumonia was observed in patients treated with FUZEON in the Phase
III clinical trials compared to the control arm. It is unclear if the
increased incidence of pneumonia is related to FUZEON use.
Roche in HIV
Roche is at the forefront of efforts to combat HIV infection and AIDS,
committed for 15 years to groundbreaking research and development of new
drugs and diagnostic technology. Roche's objective is to provide tailored
treatment solutions and an improved standard of care worldwide for people
living with HIV.
About Roche
Hoffmann-La Roche (Roche), based in Nutley, N.J., is the U.S. prescription
drug unit of the Roche Group, a leading research-based health care enterprise
that ranks among the world's leaders in pharmaceuticals, diagnostics and
vitamins. Roche discovers, develops, manufactures and markets numerous
important prescription drugs that enhance people's health, well being and
quality of life. Among the company's areas of therapeutic interest are:
dermatology; genitourinary disease; infectious diseases, including influenza;
inflammation, including arthritis and osteoporosis; metabolic diseases,
including obesity and diabetes; neurology; oncology; transplantation;
vascular diseases; and virology, including HIV/AIDS and hepatitis C.
For more information on the Roche pharmaceuticals business in the United
States, visit the company's Web site at: http://www.rocheusa.com.M
About Trimeris, Inc.
Trimeris, Inc. (Nasdaq: TRMS) is a biopharmaceutical company engaged in the
discovery, development and commercialization of novel therapeutic agents for
the treatment of viral disease. The core technology platform of fusion
inhibition is based on blocking viral entry into host cells. FUZEONä, just
approved by the FDA, is the first in a new class of anti-HIV drugs called
fusion inhibitors. A Marketing Authorisation Application (MAA) has also been
submitted for FUZEON in the European Union. Trimeris' second fusion
inhibitor product candidate, T-1249, has received fast track status from the
FDA and is in Phase I/II clinical testing. Trimeris is developing FUZEON and
T-1249 in collaboration with F. Hoffmann-La Roche Ltd. For more information
about Trimeris, please visit the company's website at www.trimeris.com.
Trimeris Safe Harbor Statement
This document and any attachments may contain forward-looking information
about the Company's financial results and business prospects that involve
substantial risks and uncertainties. These statements can be identified by
the fact that they use words such as "expect," "project," "intend," "plan,"
"believe" and other words and terms of similar meaning. Among the factors
that could cause actual results to differ materially are the following:
there is uncertainty regarding the success of research and development
activities, regulatory authorizations and product commercializations; the
results of our previous clinical trials are not necessarily indicative of
future clinical trials; and, our drug candidates are based upon novel
technology, are difficult and expensive to manufacture and may cause
unexpected side effects. For a detailed description of these factors, see
Trimeris' Form S-3 filed with the Securities and Exchange Commission on
September 27, 2002 and its periodic reports filed with the SEC.
New England Journal of Medicine Fuzeon Report
This report released upon approval of T-20 and published in current NEJM
issue.
Enfuvirtide, an HIV-1 Fusion Inhibitor, for Drug-Resistant HIV Infection in
North and South America: results from T-20 study TORO I
Study authors: Jacob P. Lalezari, M.D., Keith Henry, M.D., Mary O'Hearn,
M.D., Julio S.G. Montaner, M.D., Peter J. Piliero, M.D., Benoit Trottier,
M.D., Sharon Walmsley, M.D., Calvin Cohen, M.D., Daniel R. Kuritzkes, M.D.,
Joseph J. Eron, Jr., M.D., Jain Chung, Ph.D., Ralph DeMasi, Ph.D., Lucille
Donatacci, M.S., Claude Drobnes, M.D., John Delehanty, Ph.D., Miklos Salgo,
M.D., Ph.D.,for the TORO 1 Study Group
ABSTRACT
Background: The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a
randomized, open-label, phase 3
study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1)
fusion inhibitor.
Methods: Patients from 48 sites in the United States, Canada, Mexico, and
Brazil with at least six months of
previous treatment with agents in three classes of antiretroviral drugs,
resistance to drugs in these classes, or both, and with at least 5000 copies
of HIV-1 RNA per milliliter of plasma were randomly assigned in a 2:1 ratio
to receive enfuvirtide plus an optimized background regimen of three to five
antiretroviral drugs or such a regimen alone (control group). The primary
efficacy end point was the change in the plasma HIV-1 RNA level from base
line to week 24.
Results: A total of 501 patients underwent randomization, and 491 received at
least one dose of study drug and had at least one measurement of plasma HIV-1
RNA after treatment began. The two groups were balanced in terms of the
median base-line HIV-1 RNA level (5.2 log10 copies per milliliter in both
groups), median CD4+ cell count (75.5 cells per cubic millimeter in the
enfuvirtide group, and 87.0 cells per cubic millimeter in the control group),
demographic characteristics, and previous antiretroviral therapy. At 24
weeks, the least-squares mean change from base line in the viral load
(intention-to-treat, last observation carried forward) was a decrease of
1.696 log10 copies per milliliter in the enfuvirtide group, and a decrease of
0.764 log10 copies per milliliter in the control group (P<0.001). The mean
increases in CD4+ cell count were 76 cells per cubic millimeter and 32 cells
per cubic millimeter, respectively (P<0.001). Reactions at the site of the
injections were reported by 98 percent of patients receiving enfuvirtide.
There were more cases of pneumonia in the enfuvirtide group than in the
control group.
Conclusions The addition of enfuvirtide to an optimized antiretroviral
regimen provided significant antiretroviral and immunologic benefit through
24 weeks in patients who had previously received multiple antiretroviral
drugs and had multidrug-resistant HIV-1 infection.
Notice: Because the FDA approved enfuvirtide on March 13, 2003, this article
has been published early at www.nejm.org. It will appear in the May 29 issue
of the Journal.
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