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Published in the Bulletin of Experimental Treatments for AIDS April 1998 issue, by the San Francisco AIDS Foundation. |
Drug Watch: FomivirsenBy Liz Highleyman Recently reported clinical trial results indicate that fomivirsen (also known as ISIS 2922; no brand name yet assigned), from Isis Pharmaceuticals of Carlsbad, CA, is a promising new treatment for cytomegalovirus (CMV) retinitis. Retinitis is an inflammation of the retina of the eye. CMV disease is one of the most feared HIV-related opportunistic infections because it can to lead to blindness. CMV can also infect the lungs, colon and brain. CMV usually only causes disease in immunocompromised people. An estimated 15-40% of people with AIDS develop CMV retinitis. The disease is usually progressive (worsens over time), and may require lifelong therapy. Clinical Trial ResultsAt the Interscience Conference on Antimicrobial Agents and Chemotherapy in September 1995, Isis researchers presented results from a Phase I/II study of fomivirsen. Data from fundus photographs of the interior of the eye indicated that the drug halted CMV retinitis progression and had a significant response duration in people with advanced CMV retinitis for whom other treatments were failing. Study results presented at the International Consensus Symposium on Advances in the Diagnosis, Treatment and Prophylaxis of CMV Infection in April 1996 showed that fomivirsen leads to rapid and prolonged remission of CMV retinitis in patients with both early and advanced disease. An uncontrolled open-label trial showed delays in progression of as long as 600 days. At the 5th Conference on Retroviruses and Opportunistic Infections (CROI), Isis presented the first reported data from a Phase III study of fomivirsen. The trial included 28 HIV positive participants who had newly diagnosed and not previously treated peripheral CMV retinitis not affecting the central part of the retina. Eighteen patients received fomivirsen immediately, while 10 were put in a deferred treatment arm that started therapy when disease progression was detected. Efficacy was assessed using fundus photographs. Retinitis progressed in a median of 71 days for the immediately treated group and in a median of 13 days in the deferred group, a statistically significant difference. DosageIn the Phase III trial reported at CROI, patients received 150 micrograms of fomivirsen injected into the eye once a week for 3 weeks. Following this induction period, maintenance doses were received every other week. An ongoing trial is studying a 330 microgram dose of fomivirsen in people with advanced, active CMV retinitis. Side EffectsResearchers reported that fomivirsen appeared safe in clinical trials. Side effects seen so far include minor vision defects, temporary increases in pressure within the eye (in 18.5% of participants) and mild-to-moderate eye inflammation (in 15%) which responded to topical corticosteroid drops. No systemic side effects have been reported, and no retinal detachments were seen. No patient left the Phase III study due to side effects. Other Treatments for CMVOther drugs used to treat CMV retinitis include cidofovir (brand name Vistide; formerly known as HPMPC), a nucleoside analog drug; ganciclovir (brand name Cytovene; formerly called DHPG); and foscarnet (brand name Foscavir). These drugs are inconvenient to administer. Ganciclovir and foscarnet may require intravenous infusion using an implanted catheter. Drugs administered systemically (to the whole body) may cause serious adverse side effects. Drugs that are administered locally, such as fomivirsen, ganciclovir eye injections and the ganciclovir eye implant (Vitrasert), generally do not cause as many side effects, although surgically placed implants can lead to complications including retinal detachment. Oral ganciclovir may be used as preventive or maintenance therapy, and may be used with other anti-CMV drugs. Antisense TherapyFomivirsen is based on antisense technology, a type of gene therapy. The drug is an oligonucleotide, a short chain of nucleotides (the building blocks of genetic material). The antisense compound works by interfering with the decoding of CMV's genetic material. In order to produce new proteins, the part of the virus' DNA that encodes a specific protein (a sense sequence) is copied to messenger RNA. Fomivirsen is a complementary (antisense) sequence that binds to the messenger RNA sequence and blocks CMV's ability to make the proteins it needs in order to replicate. Unlike many antiviral drugs, the compound does not interfere with human DNA. Because it is more specific to CMV, fomivirsen produces less severe side effects. Also, because of the way in which the antisense drug interferes with viral replication, it is expected that CMV will not be able to develop resistance to fomivirsen. Fomivirsen is the first antisense oligonucleotide drug to show clinical activity in humans, and is the most advanced antisense drug in clinical development. In January 1998, Isis began clinical trials of a second generation antisense compound for CMV disease called ISIS 13312. The company is also working on antisense drugs for Crohn's disease and cancer. Access to FomivirsenIsis is collaborating with CIBA Vision to distribute fomivirsen. The companies will use data from Phase III studies to support a New Drug Application to the Food and Drug Administration. Preparation of the NDA is currently underway and is expected to be submitted in the first half of this year. European regulatory filing will take place at about the same time. Isis is also conducting ongoing clinical trials of fomivirsen. For information, see the company's website at www.isip.com. Liz Highleyman is Assistant Editor of BETA.
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