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FUZEON (T-20) Approved by the FDA
  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
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:
T-20 and T-1249: report from ICAAC Conference on how co-factors in success using T-20
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 (≤1 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. FUZEONš, 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
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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