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Fomiversen Sodium Approved to Treat CMV Retinitis
y
Forniversen Sodiulll Approved to Treat CMV Retinitis Peggy Piascik
In August 1998, the Food and Drug Administration approved fomivirsen sodium (Vitravene--Isis Pharmaceuticals, Inc., Carlsbad, Calif.; and CmA Vision Ophthalmics, Atlanta) for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Vitravene was reviewed under the priority review process reserved for therapies that promise to substantially improve the standard of treatment for a particular disease or condition. Vitravene is the fIrst antisense product approved as a therapeutic agent. Fomivirsen has been described by Dr. R. M. Lieberman, an ophthalmologist who participated in clinical trials, as "easy, fast, and
painless to administer, patients respond rapidly, and the drug keeps the disease in check for extended periods in selected groups of patients."l Advantages of the new agent in the management of CMV retinitis include avoidance of intravenous lines and the systemic toxicities of intravenous therapies, and decreased frequency of injections compared with other antiviral compounds.
CMV Retinitis In immunocompetent adults, CMV, a herpes virus, commonly causes mild or subclinical infection and requires no subsequent treatment. However, CMV is opportunistic in immunocomprornised individ-
Figure 1. How Fomiversen Works Oi Ii Ii 01. Ii Ii C4IIy&in g Pr~kin Ii
lmrocription
-+
84 J
Tranllatlon
urnaJ f th Am rican PhannaceuticaJ Association
ual , uch as transplant recipients and AIDS patients, who cannot mount a vigorous immune response. The disease occurs in an estimated 15% to 40% of patients with AIDS,2,3 resulting in the gradual destruction of the light-sensitive tissue of the eye and eventual loss of vision. Despite treatment, some degree of visual loss occurs in nearly all patients with a diagnosis of CMV retinitis.4 Forni virsen is intended for local treatment of CMV retinitis in patients with AIDS who cannot tolerate, who have a contraindication to, or who do not sufficiently respond to other treatments. The recommended labeled dosage consists of an induction dose of 330 mcg on days 1 and 15 of therapy followed by a monthly intravitreal injection of 330 mcg. Intravitreal injection requires that an ophthalmologist administer the drug direct1y into the eye.
Other Drugs Used to Treat CMV Retinitis The antiviral agents currently used to treat CMV retinitisintravenous or oral ganciclovir (Cytovene-Roche), gancidovir implant (Vitrasert Implant-Bausch & Lomb; Chiron Vision), cidofovir (Vistide-Gilead Sciences), and foscamet (Foscavir-Astra)are virustatic rather than virucidal. Clinical resistance to one of these three drugs usually indicates reduced clinical utility of the others because of their shared mechanism of action, inhibition of DNA polymerase. Disadvantages of the use of these agents include renal toxicity and the need for an
indwelling catheter for intravenou lyadmini tered ganciclovir and foscamet. U e of a surgically implanted, controlled-release, pelletized formulation of ganciclovir (Vitrasert--Roche Biosciences; Chiron Vision) is limited by high cost, repeated surgeries, and a retinal detachment rate up to 28% in clinical trials (Chiron Vision, unpublished, 1996).
Antisense Drugs Antisense drugs such as fomivirsen inhibit the production of disease-causing proteins. These agents can treat a wide range of diseases, including infectious, inflammatory, and cardiovascular diseases and cancer, and have the potential to be more selective, more effective, and less toxic than drugs used traditionally to treat certain diseases. To understand how antisense drugs work, it is necessary to review the process of intracellular protein production (Figure 1). The fIrst step in the production of a specific protein is for the two complementary strands of DNA that code for that protein to begin uncoiling within the nucleus. The "sense" strand, or the strand that carries the Biotechnology Update is developed by the American Pharmaceutical Association, edited by Peggy Piascik, PhD, University of Kentucky College of Phannac~andsupporled
by an educational grant from Amgen Inc. The views expressed are not necessarily those of Amgen.
AttGEN. January/February 1999
Vol. 39, No.1
BIOTECHNOLOGY UPDATE
m sage of how to mble pecific amino acids into the protein tructure epara from the "anti ense' trand. The antisen e strand of DNA i then used as a template for as embling a complementary trand of mes enger RNA (mRNA) by a process called transcription. This complementary strand of roRNA migrates into the cytoplasm, where the ribosomes read the information encoded in the mRNA base sequence and string together amino acids to form a specific protein. This process is called translation. Antisense drugs are short chains of nucleotides, called oligonucleotides, designed to bind to a specific sequence of nucleotides in an rnRNA target, thereby inhibiting translation and the production of the protein encoded by the target rnRNA. Antisense drugs act at an early stage in the production of a disease-causing protein, whereas traditional drugs normally act after the disease-causing protein has been produced.
un hanged b the pr e and pr eed to find another complementary en e trand of mRNA beginning the proce again. Thu the protein mediator that lead to CMV retiniti i not produced, and di ease progre ion low or top .
Results of Clinical Trials Phase ill trials were conducted in both newly diagnosed patients and patients who failed treatment with other agents. The median time to CMV retinitis progression was approximately 80 days in patients treated with the recommended dose of 330 mcg. The trial demonstrated that a monthly dose of fomivirsen delays progression of advanced disease. Although no studies involving direct comparisons of older antiviral agents with fomivirsen have been conducted to date, these results compare favorably with published results from other agents.
have been treated with cidofovir within two to four weeks, becau e of the increased risk of ocular inflammation. Intravitreall y administered fomivirsen will not be effective against contralateral CMV retinitis unless it is administered to both eyes. It will not affect the systemic CMV disease that may occur in AIDS patients with CMV retinitis. Fomivirsen may be administered concomitantly with systemic ganciclovir to provide systemic anti-CMV coverage. In some patients the disease will progress during or following treatment. Therefore, follow-up procedures should include regular ophthalmologic exams. HIV -infected patients should continue taking other medications, such as antiretroviral therapy, as prescribed. This protein should be stored between 2°C to 25°C (35°C to 77°F) and protected from light.
for patients with advanced disease comparing two dosage schedules of fomivirsen injected intravitreally.
More Antisense Drugs in the Future Fomivirsen is the fIrst product of antisense technology to reach the market as a therapeutic agent. Antisense drugs active against a wide range of infectious, inflammatory, and immune-mediated diseases, and against cancers, are in various stages of development. One antisense compound currently in clinical trials is being tested for use in Crohn's disease, psoriasis, rheumatoid arthritis, and ulcerative colitis. Other drugs are being tested for treatment of cardiovascular restenosis and renal transplant rejection. Peggy Piascik, PhD, is associate professor of pharmacy practice and science at the University of Kentucky College of Pharmacy in Lexington.
Continuing Trials How Fomivirsen Works CMV attacks target cells in the retina and begins replicating itself using the machinery of the human DNA (see Figure 1). Fomivirsen inhibits the expression of two proteins necessary for viral replication. Fornivirsen is complementary to and binds to the sense strand of mRNA, which codes for the targeted proteins. This creates a complex that is recognized by another enzyme, RNAse H. This enzyme joins with the rnRNNantisense complex, altering the mRNA and causing it to decompose, rendering it ineffective. Fomivirsen is
Vol. 39, No.1
J anuarylFebruary 1999
Adverse Effects The most frequently reported ocular side effects were transient increases in intraocular pressure and mild-to-moderate intraocular inflammation. Intraocular pressure usually returns to the normal range without treatment or with temporary use of topical medications. Inflammation has been reported in approximately one in four patients, usually during the induction phase of therapy. Using topical corticosteroids and delaying further injections until inflammation has resolved allows most patients to continue therapy. Vitravene should not be used in patients who
Fomivirsen continues to be studied for broadened uses as an anti-CMV agent. Prospective, controlled clinical trials underway for a range of CMV retinitis stages include the following: • An open, randomized trial for patients with early, peripheral disease. Patients are randomized to delayed versus immediate therapy with fomi virsen and the time to fIrst progression is measured. • An open, randomized trial comparing patients induced with intravenous gancidovir and maintained on oral gancidovir with patients induced and maintained with fomivirsen and oral gancidovir, respectively. • An open, randomized trial
References 1. Association for Vision Research and Ophthalmology. ARVO presentations show safety and efficacy of Isis' CMV retinitis drug. [press releasel. Isis Pharmaceuticals, May 15, 1997. 2. Jabs DA, Green WR, Fox R, et al. Ocular manifestations of acquired immune deficiency syndrome . Ophthalmology. 1989;96(7): 1092-9. 3. Henderly DE, Freeman WR, Smith RE, et al. Cytomegalovirus retinitis as the initial m anifestation of the acquired imm une deficiency synd rome. Am J Ophthalmol. 1987; 103:316-20. 4. SOCA. Foscarnet-ganciclovir cyto megal ovirus retinitis trial: 4. Visual outcomes. Studies of Ocular Complications of AIDS (SOCA) Re sea rc h Group i n co lla bo ration w ith the AIDS Clinical Trials Group. Ophthalmology. 1994;1 01 (7): 1250-61.
Journal of the American Pharmaceutical Association
85
Forniversen Sodiulll Approved to Treat CMV Retinitis Peggy Piascik
In August 1998, the Food and Drug Administration approved fomivirsen sodium (Vitravene--Isis Pharmaceuticals, Inc., Carlsbad, Calif.; and CmA Vision Ophthalmics, Atlanta) for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. Vitravene was reviewed under the priority review process reserved for therapies that promise to substantially improve the standard of treatment for a particular disease or condition. Vitravene is the fIrst antisense product approved as a therapeutic agent. Fomivirsen has been described by Dr. R. M. Lieberman, an ophthalmologist who participated in clinical trials, as "easy, fast, and
painless to administer, patients respond rapidly, and the drug keeps the disease in check for extended periods in selected groups of patients."l Advantages of the new agent in the management of CMV retinitis include avoidance of intravenous lines and the systemic toxicities of intravenous therapies, and decreased frequency of injections compared with other antiviral compounds.
CMV Retinitis In immunocompetent adults, CMV, a herpes virus, commonly causes mild or subclinical infection and requires no subsequent treatment. However, CMV is opportunistic in immunocomprornised individ-
Figure 1. How Fomiversen Works Oi Ii Ii 01. Ii Ii C4IIy&in g Pr~kin Ii
lmrocription
-+
84 J
Tranllatlon
urnaJ f th Am rican PhannaceuticaJ Association
ual , uch as transplant recipients and AIDS patients, who cannot mount a vigorous immune response. The disease occurs in an estimated 15% to 40% of patients with AIDS,2,3 resulting in the gradual destruction of the light-sensitive tissue of the eye and eventual loss of vision. Despite treatment, some degree of visual loss occurs in nearly all patients with a diagnosis of CMV retinitis.4 Forni virsen is intended for local treatment of CMV retinitis in patients with AIDS who cannot tolerate, who have a contraindication to, or who do not sufficiently respond to other treatments. The recommended labeled dosage consists of an induction dose of 330 mcg on days 1 and 15 of therapy followed by a monthly intravitreal injection of 330 mcg. Intravitreal injection requires that an ophthalmologist administer the drug direct1y into the eye.
Other Drugs Used to Treat CMV Retinitis The antiviral agents currently used to treat CMV retinitisintravenous or oral ganciclovir (Cytovene-Roche), gancidovir implant (Vitrasert Implant-Bausch & Lomb; Chiron Vision), cidofovir (Vistide-Gilead Sciences), and foscamet (Foscavir-Astra)are virustatic rather than virucidal. Clinical resistance to one of these three drugs usually indicates reduced clinical utility of the others because of their shared mechanism of action, inhibition of DNA polymerase. Disadvantages of the use of these agents include renal toxicity and the need for an
indwelling catheter for intravenou lyadmini tered ganciclovir and foscamet. U e of a surgically implanted, controlled-release, pelletized formulation of ganciclovir (Vitrasert--Roche Biosciences; Chiron Vision) is limited by high cost, repeated surgeries, and a retinal detachment rate up to 28% in clinical trials (Chiron Vision, unpublished, 1996).
Antisense Drugs Antisense drugs such as fomivirsen inhibit the production of disease-causing proteins. These agents can treat a wide range of diseases, including infectious, inflammatory, and cardiovascular diseases and cancer, and have the potential to be more selective, more effective, and less toxic than drugs used traditionally to treat certain diseases. To understand how antisense drugs work, it is necessary to review the process of intracellular protein production (Figure 1). The fIrst step in the production of a specific protein is for the two complementary strands of DNA that code for that protein to begin uncoiling within the nucleus. The "sense" strand, or the strand that carries the Biotechnology Update is developed by the American Pharmaceutical Association, edited by Peggy Piascik, PhD, University of Kentucky College of Phannac~andsupporled
by an educational grant from Amgen Inc. The views expressed are not necessarily those of Amgen.
AttGEN. January/February 1999
Vol. 39, No.1
BIOTECHNOLOGY UPDATE
m sage of how to mble pecific amino acids into the protein tructure epara from the "anti ense' trand. The antisen e strand of DNA i then used as a template for as embling a complementary trand of mes enger RNA (mRNA) by a process called transcription. This complementary strand of roRNA migrates into the cytoplasm, where the ribosomes read the information encoded in the mRNA base sequence and string together amino acids to form a specific protein. This process is called translation. Antisense drugs are short chains of nucleotides, called oligonucleotides, designed to bind to a specific sequence of nucleotides in an rnRNA target, thereby inhibiting translation and the production of the protein encoded by the target rnRNA. Antisense drugs act at an early stage in the production of a disease-causing protein, whereas traditional drugs normally act after the disease-causing protein has been produced.
un hanged b the pr e and pr eed to find another complementary en e trand of mRNA beginning the proce again. Thu the protein mediator that lead to CMV retiniti i not produced, and di ease progre ion low or top .
Results of Clinical Trials Phase ill trials were conducted in both newly diagnosed patients and patients who failed treatment with other agents. The median time to CMV retinitis progression was approximately 80 days in patients treated with the recommended dose of 330 mcg. The trial demonstrated that a monthly dose of fomivirsen delays progression of advanced disease. Although no studies involving direct comparisons of older antiviral agents with fomivirsen have been conducted to date, these results compare favorably with published results from other agents.
have been treated with cidofovir within two to four weeks, becau e of the increased risk of ocular inflammation. Intravitreall y administered fomivirsen will not be effective against contralateral CMV retinitis unless it is administered to both eyes. It will not affect the systemic CMV disease that may occur in AIDS patients with CMV retinitis. Fomivirsen may be administered concomitantly with systemic ganciclovir to provide systemic anti-CMV coverage. In some patients the disease will progress during or following treatment. Therefore, follow-up procedures should include regular ophthalmologic exams. HIV -infected patients should continue taking other medications, such as antiretroviral therapy, as prescribed. This protein should be stored between 2°C to 25°C (35°C to 77°F) and protected from light.
for patients with advanced disease comparing two dosage schedules of fomivirsen injected intravitreally.
More Antisense Drugs in the Future Fomivirsen is the fIrst product of antisense technology to reach the market as a therapeutic agent. Antisense drugs active against a wide range of infectious, inflammatory, and immune-mediated diseases, and against cancers, are in various stages of development. One antisense compound currently in clinical trials is being tested for use in Crohn's disease, psoriasis, rheumatoid arthritis, and ulcerative colitis. Other drugs are being tested for treatment of cardiovascular restenosis and renal transplant rejection. Peggy Piascik, PhD, is associate professor of pharmacy practice and science at the University of Kentucky College of Pharmacy in Lexington.
Continuing Trials How Fomivirsen Works CMV attacks target cells in the retina and begins replicating itself using the machinery of the human DNA (see Figure 1). Fomivirsen inhibits the expression of two proteins necessary for viral replication. Fornivirsen is complementary to and binds to the sense strand of mRNA, which codes for the targeted proteins. This creates a complex that is recognized by another enzyme, RNAse H. This enzyme joins with the rnRNNantisense complex, altering the mRNA and causing it to decompose, rendering it ineffective. Fomivirsen is
Vol. 39, No.1
J anuarylFebruary 1999
Adverse Effects The most frequently reported ocular side effects were transient increases in intraocular pressure and mild-to-moderate intraocular inflammation. Intraocular pressure usually returns to the normal range without treatment or with temporary use of topical medications. Inflammation has been reported in approximately one in four patients, usually during the induction phase of therapy. Using topical corticosteroids and delaying further injections until inflammation has resolved allows most patients to continue therapy. Vitravene should not be used in patients who
Fomivirsen continues to be studied for broadened uses as an anti-CMV agent. Prospective, controlled clinical trials underway for a range of CMV retinitis stages include the following: • An open, randomized trial for patients with early, peripheral disease. Patients are randomized to delayed versus immediate therapy with fomi virsen and the time to fIrst progression is measured. • An open, randomized trial comparing patients induced with intravenous gancidovir and maintained on oral gancidovir with patients induced and maintained with fomivirsen and oral gancidovir, respectively. • An open, randomized trial
References 1. Association for Vision Research and Ophthalmology. ARVO presentations show safety and efficacy of Isis' CMV retinitis drug. [press releasel. Isis Pharmaceuticals, May 15, 1997. 2. Jabs DA, Green WR, Fox R, et al. Ocular manifestations of acquired immune deficiency syndrome . Ophthalmology. 1989;96(7): 1092-9. 3. Henderly DE, Freeman WR, Smith RE, et al. Cytomegalovirus retinitis as the initial m anifestation of the acquired imm une deficiency synd rome. Am J Ophthalmol. 1987; 103:316-20. 4. SOCA. Foscarnet-ganciclovir cyto megal ovirus retinitis trial: 4. Visual outcomes. Studies of Ocular Complications of AIDS (SOCA) Re sea rc h Group i n co lla bo ration w ith the AIDS Clinical Trials Group. Ophthalmology. 1994;1 01 (7): 1250-61.
Journal of the American Pharmaceutical Association
85